Academic literature on the topic 'Acidic tumor microenvironment'
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Journal articles on the topic "Acidic tumor microenvironment"
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Qu, Fanli, Guanwen Wang, Ningning Zhang, Qing Shao, and Xiaohua Zeng. "Abstract P3-02-29: The mechanism of acidic microenvironment promotes tumor-associated macrophages secreting glutamine to activate dual signaling pathways of mTORC1 and c-MYC in CDK4/6 inhibitor resistance of ER-positive breast cancer." Clinical Cancer Research 31, no. 12_Supplement (2025): P3–02–29—P3–02–29. https://doi.org/10.1158/1557-3265.sabcs24-p3-02-29.
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Abstract Resistance to CDK4/6 inhibitors in ER-positive breast cancer poses a clinical challenge, and the underlying mechanisms remain unclear. ER serves as a crucial regulator of glycolysis, promoting tumor progression and resistance by inducing microenvironmental acidification. We observed that an acidic microenvironment induces the polarization of tumor-associated macrophage (TAM) toward the M2 phenotype, leading to the secretion of glutamine. This activation of mTOR promotes resistance to CDK4/6 inhibitors in ER-positive breast cancer. Concurrently, glutamine promotes the upregulation of c-MYC in breast cancer cells, inducing lactate production and exacerbating microenvironmental acidification. We propose a scientific hypothesis: the acidic microenvironment drives TAM towards M2 polarization, secreting glutamine. This, in turn, activates both mTOR and c-MYC pathways, promoting resistance to CDK4/6 inhibitors and intensifying tumor microenvironment acidification. Through in vivo and in vitro experiments, we aim to elucidate the role of M2 macrophages in CDK4/6 inhibitor resistance under acidic conditions. We seek to clarify the molecular mechanisms by which M2 macrophages secrete glutamine, mediating CDK4/6 inhibitor resistance in ER-positive breast cancer and worsening microenvironmental acidification. Additionally, we aim to evaluate the sensitizing effects of targeting the acidic microenvironment and glutamine. Successful completion of this study holds the potential to provide a scientific basis for establishing novel approaches to overcome CDK4/6 inhibitor resistance in ER-positive breast cancer. Citation Format: Fanli Qu, Guanwen Wang, Ningning Zhang, Qing Shao, Xiaohua Zeng. The mechanism of acidic microenvironment promotes tumor-associated macrophages secreting glutamine to activate dual signaling pathways of mTORC1 and c-MYC in CDK4/6 inhibitor resistance of ER-positive breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-02-29.
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Böhme, Ines, and Anja Katrin Bosserhoff. "Acidic tumor microenvironment in human melanoma." Pigment Cell & Melanoma Research 29, no. 5 (2016): 508–23. http://dx.doi.org/10.1111/pcmr.12495.
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Feng, Liangzhu, Ziliang Dong, Danlei Tao, Yicheng Zhang, and Zhuang Liu. "The acidic tumor microenvironment: a target for smart cancer nano-theranostics." National Science Review 5, no. 2 (2017): 269–86. http://dx.doi.org/10.1093/nsr/nwx062.
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Abstract The acidic tumor microenvironment (TME), which mainly results from the high glycolytic rate of tumor cells, has been characterized as a hallmark of solid tumors and found to be a pivotal factor participating in tumor progression. Recently, due to the increasing understanding of the acidic TME, it has been shown that the acidic TME could be utilized as a multifaceted target during the design of various pH-responsive nanoscale theranostic platforms for the precise diagnosis and effective treatment of cancers. In this article, we will give a focused overview on the latest progress in utilizing this characteristic acidic TME as the target of nano-theranostics to enable cancer-specific imaging and therapy. The future perspectives in the development of acidic TME-targeting nanomedicine strategies will be discussed afterwards.
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Liu, Yu-Cheng, Zhi-Xian Wang, Jing-Yi Pan, et al. "Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics." Molecules 28, no. 5 (2023): 2175. http://dx.doi.org/10.3390/molecules28052175.
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The acidic extracellular microenvironment has become an effective target for diagnosing and treating tumors. A pH (low) insertion peptide (pHLIP) is a kind of peptide that can spontaneously fold into a transmembrane helix in an acidic microenvironment, and then insert into and cross the cell membrane for material transfer. The characteristics of the acidic tumor microenvironment provide a new method for pH-targeted molecular imaging and tumor-targeted therapy. As research has increased, the role of pHLIP as an imaging agent carrier in the field of tumor theranostics has become increasingly prominent. In this paper, we describe the current applications of pHLIP-anchored imaging agents for tumor diagnosis and treatment in terms of different molecular imaging methods, including magnetic resonance T1 imaging, magnetic resonance T2 imaging, SPECT/PET, fluorescence imaging, and photoacoustic imaging. Additionally, we discuss relevant challenges and future development prospects.
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Hasegawa, Manami, Keisuke Maede, Miyuki Nishida, et al. "Abstract 1511: Cancer adaptation to acidic tumor microenvironment." Cancer Research 85, no. 8_Supplement_1 (2025): 1511. https://doi.org/10.1158/1538-7445.am2025-1511.
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Cancer cells exhibit a characteristic metabolic pattern known as the Warburg effect, which upregulates glycolysis even in aerobic environments. As a result, cancer cells are exposed to an acidic environment due to enhanced excretion of proton and lactate. We have previously reported that this acidic tumor microenvironment induces the activation of the cholesterol biosynthesis pathway and the accumulation of N1-acetylspermidine. Although the acidic tumor microenvironment is known to suppress cancer cell proliferation, the survival strategies employed by cancer cells under such harsh conditions remain unclear. This study aims to elucidate the cell death pathways triggered by acidic pH using an environment even more acidic than physiological conditions and to reveal how cancer cells evade such cell death under physiological conditions. Live imaging was performed by exposing the cervical cancer cell line HeLa to an acidic environment (pH 5.6), which confirmed that cell death with membrane rapture was induced. Furthermore, in the pancreatic cancer cell line PANC1, phosphorylation of RIP1 and MLKL was observed, and cell death was suppressed by treatment with Nec-1, an inhibitor of RIP1. These findings identified Necroptosis induced under pH5.6.In addition, PANC1 cells that transitioned to a floating state under acidic conditions (pH 5.6-6.8) regained their adhesion and proliferation abilities when cultured under normal tissue pH conditions (pH 7.4). These findings indicate that some of the floating cells under acidic conditions avoid cell death and adopt certain survival strategies. Then, RNA-seq was performed on cells fractionated into those in suspension and those remaining adherent under pH6.8. Pathways related to the acquisition of stemness such as HDACs deacetylation pathway and PRC2 methylation pathway were observed to be active in the floating cells. Furthermore, the upregulation of EMT transcription factors was also confirmed. Furthermore, we cultured PANC1 cells under pH6.8, using a genome-wide CRISPR-Cas9 knockout screening system over a 30-day time course and identified key genes essential for the acquisition of tolerance to acidic tumor microenvironment. We elucidated a mechanism in pancreatic cancer cells whereby Necroptosis is avoided in physiologically acidic environments. This cell death-avoidance pathways under acidic conditions could potentially be applied to the development of novel therapeutic strategies that induce cell death in pancreatic cancer cells, which are highly influenced by the tumor microenvironment, particularly in acidic conditions. Citation Format: Manami Hasegawa, Keisuke Maede, Miyuki Nishida, Xu Bo, Sho Aki, Rika Tsuchida, Tsuyoshi Osawa. Cancer adaptation to acidic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1511.
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Jin, Haojie, Ning Wang, Cun Wang, and Wenxin Qin. "MicroRNAs in hypoxia and acidic tumor microenvironment." Chinese Science Bulletin 59, no. 19 (2014): 2223–31. http://dx.doi.org/10.1007/s11434-014-0273-y.
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Sharma, Vishal, та Jagdeep Kaur. "Acidic environment could modulate the interferon-γ expression: Implication on modulation of cancer and immune cells’ interactions". Asian Biomedicine 17, № 2 (2023): 72–83. http://dx.doi.org/10.2478/abm-2023-0047.
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Abstract Background In rapidly growing solid tumors, insufficient vascularization and poor oxygen supply result in an acidic tumor microenvironment, which can alter immune response. Objective To investigate the role of the acidic microenvironment in immune response modulation along with cancer and immune cells’ interactions. Method To mimic the tumor microenvironment conditions, T cells (Jurkat), macrophages (THP-1), and HeLa (cervical) cells were cultured under acidic conditions (pH 6.9, pH 6.5) and physiological pH (7.4). The HeLa cell culture medium was exploited as a tumor cell conditioned medium. Real-time PCR was carried out to quantify the mRNA levels, while flow cytometry and western blot hybridization was carried out to ascertain the levels of different proteins. Results The acidic microenvironment around the T cells (Jurkat) and macrophage cells (THP-1) could lead to the downregulation of the interferon gamma (IFN-γ). An increase in IFN-γ expression was observed when Jurkat and macrophage cells were cultured in HeLa cells conditioned medium (HCM) at low pH (pH 6.9, pH 6.5). The HeLa cells under acidic environment (pH 6.9, pH 6.5) upregulated interleukin 18 levels and secreted it as exosome anchored. Additionally, enhanced nuclear localization of NF-κB was observed in Jurkat and THP-1 cells cultured in HCM (pH 6.9, pH 6.5). Jurkat and THP-1 cultured in HCM revealed enhanced cytotoxicity against the HeLa cells upon reverting the pH of the medium from acidic to physiological pH (pH 7.4). Conclusion Collectively, these results suggest that the acidic microenvironment acted as a key barrier to cancer and immune cells’ interactions.
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Boedtkjer, Ebbe, and Stine F. Pedersen. "The Acidic Tumor Microenvironment as a Driver of Cancer." Annual Review of Physiology 82, no. 1 (2020): 103–26. http://dx.doi.org/10.1146/annurev-physiol-021119-034627.
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Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
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Wayne Chang, Wun-Shaing. "Abstract B002: Dynamic response and evolving adaptation of pancreatic cancer cells to the prolonged acidic pH microenvironment." Cancer Research 84, no. 22_Supplement (2024): B002. http://dx.doi.org/10.1158/1538-7445.tumbody-b002.
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Abstract Solid tumor cells are often immersed in an acidic microenvironment. While many previous studies have investigated the short-term effects of extracellular acidity on tumor cells, little is known about how they adapt to the prolonged acidic microenvironmental stress and then advance to more aggressive stages. By challenging pancreatic tumor cells as an example with continuously and gradually acidified extracellular pH, a variety of cellular characteristics including phenotypic regulation, proliferation rates, autophagic control, metabolic plasticity and metastatic potentials were identified. More detailed evidence regarding the mitochondrial network dynamics and mechanistic control of pancreatic tumor cells in response to the extracellular acidosis will be presented at this conference to emphasize the critical effects of this stress factor as a selection force for tumor adaptation and progression. These findings not only highlight the importance of dynamic response and evolving adaptation of solid tumor cells to the chronic microenvironmental acidity, but also the potential of targeting the 'acid-mediated tumor malignancy' for anticancer therapy. Citation Format: Wun-Shaing Wayne Chang. Dynamic response and evolving adaptation of pancreatic cancer cells to the prolonged acidic pH microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B002.
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Kyriazi, Athina A., Makrina Karaglani, Sofia Agelaki, and Stavroula Baritaki. "Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?" Cells 13, no. 15 (2024): 1279. http://dx.doi.org/10.3390/cells13151279.
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The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tumor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multileveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely, the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multileveled and multifaceted manner.
Dissertations / Theses on the topic "Acidic tumor microenvironment"
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Audero, Madelaine. "Acidic tumor microenvironment and Ca2+ signaling interplay in Pancreatic Ductal Adenocarcinoma (PDAC) progression." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS105.
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L'adénocarcinome canalaire pancréatique (PDAC) est une maladie mortelle caractérisée par un micro-environnement tumoral (TME) extrêmement acide (˂pHe 6,5) qui joue un rôle important dans son début et sa progression. Dans ce contexte, les canaux ioniques perméables au Ca2+ représentent de bons candidats cibles en raison de leur capacité à intégrer des signaux provenant de la TME. Les canaux Ca2+ sont en effet des capteurs de pH capables d'intégrer les signaux de la TME pour activer les voies intracellulaires en aval liées à la progression du PDAC. Bien que les rôles de l'acidose tumorale et de la signalisation du Ca2+ dans la progression du cancer soient bien établis, l'hypothèse d'une TME acide utilisant la signalisation du Ca2+ comme voie préférentielle pour soutenir la progression tumorale n'a pas encore été suffisamment explorée.Mon travail de doctorat visait à étudier les changements phénotypiques et génétiques des cellules PDAC lors d'un stress acide au cours des différentes étapes de sélection et à évaluer comment l'acidose tumorale module les signaux Ca2+ et les phénotypes dans les lignées cellulaires PDAC, avec un accent particulier sur les oscillations Ca2+ et Store-Operated Ca2+ entry (SOCE). À cette fin, les cellules PANC-1 et Mia PaCa-2 ont été soumises à une pression acide à court et à long terme et à une récupération à pHe 7,4. Ce dernier traitement visait à imiter les bords du PDAC et l'évasion consécutif des cellules cancéreuses de la tumeur. L'impact de l'acidose a été évalué sur la morphologie cellulaire, la prolifération, l'adhésion, la migration, l'invasion, l'activité des invadopodes et la transition épithélio-mésenchymateuse (TEM) par des tests fonctionnels in vitro et le séquençage de l'ARN, ainsi que sur les signaux Ca2+ intracellulaires avec Fura-2. Nos résultats indiquent qu'un court traitement acide limite la croissance, l'adhésion, l'invasion et la viabilité des cellules PDAC. Au fur et à mesure que le traitement acide progresse, il sélectionne les cellules cancéreuses ayant des capacités de migration et d'invasion accrues induites par l'EMT, ce qui augmente encore leur potentiel métastatique lorsqu'elles sont réexposées à un pHe 7,4. L'analyse RNA-seq des cellules PANC-1 exposées à une acidose de courte durée et récupérées à pHe 7,4 a révélé un recâblage transcriptomique distinct. Il est intéressant de noter que les cellules PANC-1 sont caractérisées par des oscillations Ca2+ plus lentes pendant une exposition à l'acide à court terme par rapport aux cellules de contrôle et par une tendance à la régulation négative d'ORAI1 au niveau de l'ARNm, tandis que l'acidose à long terme et le rétablissement à un pH neutre déterminent le rétablissement d'oscillations Ca2+ rapides et la régulation positive d'ORAI1. Dans tous nos modèles cellulaires, les oscillations du Ca2+ sont dépendantes de SOCE, car le blocage d'ORAI1 par Synta66 et siORAI1 entraîne une altération de l'initiation et du maintien des oscillations du Ca2+. Ces données sont en corrélation avec le SOCE dans les cellules PANC-1, qui est diminuée pendant le traitement acide à court terme, et augmentée dans les cellules sélectionnées pour l'acide avec et sans récupération à pHe 7,4. Enfin, l'entrée de Ca2+ médiée par ORAI1 pourrait être impliquée dans l'activation des cascades de signalisation qui conduisent à l'augmentation de la migration et de l'invasion de tous les modèles cellulaires exposés à un pHe acide, car le traitement par Synta66 et siORAI1 n'ont pas affecté l'invasion et la migration des cellules de contrôle.En conclusion, nos résultats montrent que la sélection induite par l'acide contribue à l'acquisition d'un phénotype plus agressif dans les cellules de PDAC, caractérisé par une augmentation du SOCE, nécessaire à la génération d'oscillations rapides de Ca2+ qui peuvent activer des voies de signalisation Ca2+-dépendantes impliquées dans la progression du PDAC<br>Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer affecting the pancreas, characterized by an unsatisfactory 5-year survival rate of around 10%, and to date, there are no effective therapeutic options for PDAC. This is in part due to a highly desmoplastic and immunosuppressive microenvironment that contributes to therapeutic failure. Moreover, the PDAC tumor microenvironment is featured by high acidosis (˂ pHe 6.5), a result of the metabolic reprogramming ("Warburg effect"), and hypoxic conditions, which offers important cues for its aggressiveness by selecting cancer cell phenotypes with competitive benefits for PDAC progression. In this context, Ca2+-permeable ion channels are known to regulate several hallmarks of cancer, including in PDAC. Therefore, they represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are indeed pH and hypoxia sensors able to transduce TME signals to activate intracellular downstream pathways linked to PDAC progression. Although the roles of tumor acidosis and Ca2+ signaling in cancer progression are well established, the hypothesis of acidic TME employing Ca2+ signaling as a preferential route for sustaining tumor progression has not yet been sufficiently explored.My Ph.D. work aimed to study the phenotypic and genetic changes of PDAC cells upon acidic stress along the different stages of selection and to evaluate how tumor acidosis modulates Ca2+ signals and phenotypes in the PDAC cell lines, with a particular focus on Ca2+ oscillations and Store-Operated Ca2+ entry (SOCE). To this end, PANC-1 and Mia PaCa-2 cells were subjected to short- and long-term acidic pressure and recovery to pHe 7.4. The latter treatment was to mimic PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, invadopodia activity, and epithelial-mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing, and for intracellular Ca2+ signals using Fura-2. Our results indicate that short acidic treatment limits the growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, thereby further enhancing their metastatic potential when re-exposed to pHe 7.4. RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We noted an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Interestingly, PANC-1 cells are characterized by slower Ca2+ oscillations during short-term acid exposure compared to control cells and a tendency of ORAI1 downregulation at mRNA levels, while long-term acidosis and recovery to neutral pHe determine the recovery of fast Ca2+ oscillations and upregulation of ORAI1. In all our cell models, Ca2+ oscillations are SOCE-dependent, as ORAI1 blockade with Synta66 and siORAI1 results in impaired Ca2+ oscillations' initiation and maintenance. These data correlate with SOCE in PANC-1 cells, which is decreased during the short-term acid treatment, and increased in acid-selected cells with and without recovery to pHe 7.4. Finally, ORAI1-mediated Ca2+ entry might be involved in the activation of signaling cascades that lead to the increased migration and invasion of all the cell models exposed to acidic pHe, as Synta66 treatment and siORAI1 didn't affect control cells' invasion and migration.In conclusion, our findings show that acid-induced selection contributes to the acquisition of a more aggressive phenotype in PDAC cells, characterized by upregulation of SOCE, required for the generation of fast Ca2+ oscillations which may trigger Ca2+-dependent signaling pathways involved in PDAC progression
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Schnipper, Julie. "The impact of the acidic tumor microenvironment on ion channel expression and regulation, in the progression of pancreatic ductal adenocarcinoma." Electronic Thesis or Diss., Amiens, 2022. http://www.theses.fr/2022AMIE0071.
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Le canal TRPC1 (pour transient receptor potential canonical 1) est l'un des canaux cationiques non sélectifs les plus impliqués dans plusieurs maladies, y compris la progression du cancer. Les TRPC peuvent être activés par différents stimuli physico-chimiques dont le pH. Par ailleurs, l'une des caractéristiques du cancer représente les variations pH extracellulaire, notamment dans l'adénocarcinome canalaire pancréatique (ACP). Il existe de fortes indications quant à l'agressivité de l'ACP qui est causée par l'interaction entre le microenvironnement acide de la tumeur et la dérégulation des canaux ioniques. Cependant, cette interaction n'a jamais été étudiée. Lors de ce travail, nous avons étudié si TRPC1 ainsi que les fluctuations du pH acide du microenvironnement tumoral régulent la progression de l'ACP et plus particulièrement la prolifération et de migration cellulaires. Nous avons constaté que TRPC1 était surexprimé dans le tissu tumoral pancréatique par rapport au tissu normal, et dans la lignée cellulaire agressive PANC-1, par rapport à une lignée cellulaire de type canalaire, hTERT-HPNE. Pour déterminer si les fluctuations du microenvironnement acide de la tumeur affectent la dérégulation de TRPC1, les cellules PANC-1 ont été incubées dans un milieu présentant un pH de 7,4 ou 6,5 pendant 30 jours, après quoi les cellules ont été récupérées à pH 7,4 pendant 14 jours (7.4 R). L'adaptation acide (6.5) a réduit l'expression de la protéine TRPC1 mais a favorisé sa localisation membranaire par rapport au contrôle (7.4). Dans des conditions de pH 7,4R, les cellules cancéreuses présentaient une expression de TRPC1 exacerbée avec une localisation membranaire élevée, à la fois dans les modèles 2D et 3D. Nous avons constaté que les fluctuations de pH et l'invalidation moléculaire par siARN (KD) de TRPC1 affectaient respectivement la prolifération de PANC-1 dans un modèle 2D et sphéroïde. Dans notre modèle 2D, nous avons montré que TRPC1 KD affectait la progression à travers la phase G0/G1 dans toutes les conditions et la phase S lorsque les cellules sont cultivées dans un milieu pH 7,4, et la phase G2/M dans les conditions pH 6,5 et 7,4 R. En outre, pH 6,5 a amélioré tandis que le KD de TRPC1 a diminué la migration cellulaire. De plus, nous avons constaté que TRPC1 interagissait fortement avec PI3K dans des conditions acides, et CaM dans toutes les conditions. Le KD de TRPC1 diminuait à la fois cette interaction et l'activation de AKT et ERK1/2. Enfin, l'entrée basale de Ca2+ a été significativement réduite par le KD de TRPC1 dans les conditions de pH 6,5 et 7,4R. La réduction de la concentration de Ca2+ extracellulaire a entraîné une diminution additionnelle de la prolifération et de la migration des cellules transfectées avec siTRPC1 cultivées à pH 6,5 et 7,4R, mais pas dans des conditions normales de pH 7,4. Collectivement, nos résultats montrent que TRPC1 est régulé positivement dans les tissus et lignées d’ACP. Le microenvironnement acide de la tumeur favorise sa localisation membranaire et son interaction avec PI3K/CaM. Enfin, le Ca2+ transitant par TRPC1 participe à la prolifération et à la migration cellulaires. De plus, nous avons effectué un criblage du profil d'expression des canaux ORAI, de leur partenaire STIM1, d'un canal sodique activé par le voltage (Nav1.6) et d'un canal ionique détectant l'acidité (ASIC1) dans les tissus et lignées d'ACP. Nous avons examiné si le microenvironnement acide affecte la régulation épigénétique des canaux ioniques. Nous avons constaté qu'ORAI3 était régulé positivement dans le tissu ACP par rapport au tissu normal, tandis que STIM1 et NaV1.6 étaient régulés négativement. De plus, ORAI3 était préférentiellement localisé au niveau membranaire dans le tissu tumoral. De plus, nos résultats préliminaires montrent que le microenvironnement acide de la tumeur n'affecte pas les niveaux de méthylation de la région promotrice des gènes codant pour ASIC1 ou TRPC1, mais également du gène SCN8A<br>The transient receptor potential canonical 1 channel (TRPC1) is one of the most prominent nonselective cation channels involved in several diseases, including cancer progression. TRPCs can be activated by different physio-chemical stimuli of their surroundings, for instance, pH. Another hallmark of cancer is the variable extracellular pH landscape, notably in epithelial cancers such as pancreatic ductal adenocarcinoma (PDAC). PDAC progression and development are linked to the physiology and microenvironment of the exocrine pancreas. There are strong indications that PDAC aggressiveness is caused by the interplay between the tumor acidic microenvironment and ion channel dysregulation. However, this interaction has never been studied before. Here, we investigate if TRPC1 is involved in PDAC progression in the form of proliferation and migration and if the pH fluctuations of the acidic tumor microenvironment affect these processes. We found that TRPC1 was significantly upregulated in PDAC tumor tissue compared to adjacent normal tissue, and in the aggressive PDAC cell line PANC-1, compared to a duct-like cell line, hTERT-HPNE. To investigate if fluctuations of the acidic tumor microenvironment affect TRPC1 dysregulation, PANC-1 cells were incubated in a medium with a pH of 7.4 or 6.5 over 30 days, where after cells were recovered in pH 7.4 for 14 days (7.4R). Acid adaptation (6.5) reduced TRPC1 protein expression but favored its membrane localization compared to the control (7.4). pH recovery treatment (7.4R) resulted in an upregulation of TRPC1 expression with a high membrane localization, both in 2D and 3D models. We found that pH fluctuations and the siRNA-based knock-down (KD) of TRPC1 affected 2D and spheroid PANC-1 proliferation, respectively. In our 2D model, flow cytometry and cell cycle regulating protein immunoblotting showed that TRPC1 KD affected the progression through G0/G1 phase under all conditions and S-phase under control pH 7.4, which shifts to the G2/M phase in pH 6.5 and 7.4R. In addition, pH 6.5 enhanced, and the KD of TRPC1 decreased cell migration, respectively. Furthermore, we found that TRPC1 interacted strongly with PI3K under acidic conditions and CaM under all conditions, and a KD of TRPC1 decreased both this interaction and the activation of AKT and ERK1/2. Finally, basal Ca2+ entry was significantly reduced upon the KD of TRPC1 in pH 6.5 and 7.4R, where the entry was enhanced. The reduction of extracellular Ca2+ concentration resulted in an additional decrease in proliferation and migration of cells transfected with siTRPC1 growing in pH 6.5 and 7.4R, but not in normal pH 7.4 conditions.Collectively, our results show that TRPC1 is upregulated in PDAC tissue and cell lines. The acidic tumor microenvironment favors its plasma membrane localization, and its interaction with PI3K/CaM and Ca2+ entry leads to PDAC cells proliferation and migration. In addition, we performed an expression profile screening of ORAI channels, their partner STIM1, and a voltage-activated sodium channel (Nav1.6), and an acid-sensing ion channel (ASIC1) in PDAC tissues and cell lines, and investigated whether the acidic tumor microenvironment affects epigenetic regulation of ion channel expression. We found that ORAI3 was upregulated in PDAC tissue compared to normal tissue, where STIM1 and NaV1.6 were significantly downregulated. Moreover, ORAI3 was more localized in the plasma membrane in tumor tissue. Acid-adaptation had a differential effect on Ca2+ channel expression. Furthermore, our preliminary results show that the acidic tumor microenvironment does not affect the methylation levels of the ASIC1 or TRPC1 promoter region, but so some extend the SCN8A gene promoter
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Assi, E. "ROLE OF ACID SPHINGOMYELINASE IN THE TUMOUR MICROENVIRONMENT." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229416.
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Defective apoptosis represents one of the major causative factors in the development and progression of cancer. The ability of tumour cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens. In the last few years, preclinical and clinical studies have indicated ceramide and the enzymes of its metabolism, in particular Acid Sphingomyelinase (A-SMase) which hydrolyzes sphingomyelin to ceramide and phosphocoline, as key players in tumour physiopathology. Different cancers have been shown to have reduced ceramide levels and, of interest, in our previous work we showed that A-SMase down-regulation was a key event in melanoma progression. This event is crucial for the tumours to become more aggressive, but the mechanisms responsible of it haven’t been investigated yet.
Taking into account that there is a complex crosstalk between tumour cells and its immunological microenvironment, in this work we first investigated its possible role in A-SMase downregulation in a melanoma model.
To this purpose we performed in vivo and in vitro experiments which led us to identify tumour associate macrophages (TAM) as possible responsible of A-SMase downregulation through the Ap2-α transcription factor. Moreover, we demonstrated that these molecular changes in tumour cells give, in turn, pro-tumoural and immunosuppressive features to the surrounding microenvironment, with the recruitment of Myeloid-derived suppressor (MDSCs) cells and Regulatory T lymphocytes (TREGS). From these and our previous data, we clearly showed that the ability to create this immunosuppression together with the acquisition of a more aggressive phenotype, both depend on the naturally occurring A-SMase decrease in melanoma cells during tumour progression.
The broad role of A-SMase in tumour pathogenesis we identified, indicates that the enzyme is at the crossroad of key pathways in tumourigenesis. This aspects has clear potential in therapeutic perspective in which A-SMase overexpression or administration might be consider as an useful adjuvant for cancer therapy.
Here we demonstrated for the first time that restoring A-SMase expression in melanoma cells not only reduces tumour growth and immunosuppression, but moreover accounts for a high, unexpected recruitment of immune cells with an anti-tumoural function in the tumour microenvironment, such as Dendritic cells (DCs) and CD4+ and CD8+ T lymphocytes.
In conclusion our results reveal the central role of A-SMase expressed by melanoma cells in orchestrating the cross-talk with the surrounding microenvironment. These interactions are crucial for tumour fate, lying on its rejection or progression. Our observation that A-SMase overexpression “educate” tumour microenvironment against cancer cells, further encourage the use of this enzyme as an adjuvant for cancer therapy.
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Al-Husari, Maymona. "Mathematical modelling of the tumour microenvironment : the causes and consequences of tumour acidity." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18965.
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Extracellular acidity and high levels of lactate are commonly observed in solid tumours. Some tumours also exhibit a reversed cellular pH gradient with an intracellular pH that is higher than the extracellular. This has been shown to play a crucial part in not only the invasive and metastatic cascade of tumours, but also on their response to therapies. In this thesis, we present four different mathematical models that examine the possible causes of tumour acidity and its effect on cell metabolism and tumour invasion. In the second chapter, we derive an ordinary differential equation model that explicitly focus on the interplay between H+-ions and lactate. We subject the model to qualitative and quantitative analysis and, in particular, we study the effect in the variations of key parameter estimates on the emergence of a reversed transmembrane pH gradient within the tumour. The model predicts that a re- versed pH gradient is attainable under aerobic conditions when sourc es of H+-ions other than those from glycolysis are decreased and the lactate/H+ cell membrane transporter (MCT) activity is increased - but we find the intra- and extracellular pH values in this case to be too alkaline to be physiological. Under anaerobic conditions, we find that decreasing the sources of H+-ions other than those from glycolysis and also the glycolytic rate gives rise to a reversed cellular pH gradient, but again for intra- and extracellular pH values that are far from realistic biologically. In the third chapter, we present an extension to the first model by including the spatial diffusion of hydrogen ions and lactate. This spatial extension also predicts ii a reversed transmembrane pH gradient but this time for more realistic intra- and extracellular pH values. We find that low levels of blood lactate can give rise to a reversed pH gradient throughout the spatial domain independent of the levels of tissue lactate. Likewise, we have found the existence of a negative pH gradient to be strongly dependent on the combined activity of a lactate/H+ cell membrane transporter and other sources of H+-ion. In the fourth chapter, we study the role of oxygen and pH on early tumour growth using a hybrid cellular automaton model. We examine whether the levels of oxygen, intra- or extracellular pH are the dominating metabolites driving tumour growth and phenotypic transformations. This model predicts that when tumour cells are strongly sensitive to changes in the intracellular pH, a low activity of the Na+/H+ cell membrane transporter (NHE) or a high rate of anaerobic glycolysis can give rise to a "fingering" morphology. Furthermore, we show that as the activity of the MCT transporter increases, all the tumour cells within the spheroid can exhibit a reversed transmembrane pH gradient. In the fifth chapter, we examine the effect of extracellular acidity on tumour invasion focusing, in particular, on cellular adhesion, matrix-degrading enz yme activity and cellular proliferation. Our numerical simulations using a cellular Potts model show that, under acidic extracellular pH, cell-ECM adhesion strength has a comparable effect on tumour invasiveness as the rate at which the ECM is degraded by proteolytic enzymes. We also show that tumour cells cultured under physiological pH tend to be larger and develop a "diffuse" morphology compared to those cultured at acidic pH which display protruding "fingers" at the advancing tumour front.
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Timosenko, Elina. "Tryptophan catabolism and amino acid transporter reprogramming in the tumour microenvironment." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:33745777-7aab-4342-b997-fc4317ec34fb.
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A large proportion of human tumours exploit tryptophan catabolism as a means to suppress T cell activity in the tumour microenvironment. However, the mechanisms that allow tumour cells to resist the detrimental effects of local tryptophan depletion have so far remained obscure. Here we demonstrate that shortage of tryptophan induced by the expression of tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) results in ATF4-dependent reprogramming of the amino acid transporter expression profile in tumour cells. Specifically, we show that tumour cells undergoing tryptophan starvation enhance the expression of several amino acid transporters including SLC1A5 and its truncated isoforms through activation of the ATF4 stress response pathway. While upregulation of SLC1A5 leads to improved glutamine and tryptophan uptake, the knockdown of this amino acid transporter inhibits tumour cell proliferation under low tryptophan conditions. In contrast to tumour cells, T cells fail to upregulate SLC1A5 during tryptophan starvation, but can enhance its expression upon cognate antigen T cell receptor engagement. SLC1A5 expression is also enriched in T regulatory cells and IDO-expressing dendritic cells, as well as in tumours growing under conditions of IDO-mediated tryptophan degradation in vivo. Finally, SLC1A5 expression correlates with IDO expression in several human tumours in silico, which is associated with poor prognosis in brain lower grade glioma. In conclusion, our results highlight key differences in the ability of tumour cells and T cells to adapt to tryptophan starvation and shed light on the previously unappreciated role of amino acid transport in IDO- and TDO-mediated immune escape.
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Silva, Lídia [Verfasser], and Rüdiger [Akademischer Betreuer] Hell. "Branched-chain amino acid metabolism in the tumor microenvironment interaction / Lidia Silva ; Betreuer: Rüdiger Hell." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177148897/34.
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Alruwaili, Waad A. "Conjugated Bile Acid and Sphingosine 1-phosophate prompt Cholangiocarcinoma Cell Growth via Releasing Exosomes." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5715.
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Cholangiocarcinoma (CCA) is a fatal primary malignancy that is formed in the bile ducts. Cancer-associated myofibroblasts play a crucial role in CCA proliferation and invasion. Furthermore, there is a growing interest in the role of the exosome in the interaction between the cancer-associated myofibroblasts and cholangiocarcinoma which lead to CCA growth. However how cholangiocarcinoma-derived exosome affect the cancer-associated myofibroblasts in the tumor microenvironment remain unknown. In this study, we examined whether exosome produced by cholangiocarcinoma could involve in the prompt of CCA cells growth by regulation of myofibroblast. We found that cholangiocarcinoma-derived exosome could prompt elevated α-smooth muscle actin and stromal cell-derived factor one expression that induces myofibroblast proliferation. We then demonstrated that cholangiocarcinoma-derived exosome upregulated periostin expression that plays an important role in cancer metastasis. In 3D organotypic rat CCA coculture model, TCA and S1P considerably increase the growth of CCA cell. Conclusion: cholangiocarcinoma-derived exosome trigger cancer-associated myofibroblasts proliferation in the tumor microenvironment that leads to prompt CCA growth.
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Dong, Jihu. "Physiopathologie de cellules souches cancéreuses isolées de glioblastomes primitifs et évaluation pré-clinique de molécules "tête de série" par une approche de biologie et de chimie médicinale." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ036/document.
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Les glioblastomes sont des tumeurs primaires du cerveau les plus malignes. L’identification des cellules souches cancéreuses de glioblastome (CSGs) a transformé notre vision globale des glioblastomes en révélant une hiérarchie cellulaire au sein de ces tumeurs. Les CSGs sont douées de propriétés d’auto-renouvellement, de différenciation et peuvent entrer en quiescence. Elles sont considérées comme les cellules entretenant les tumeurs, responsables de leur dissémination et des rechutes après traitement. La découverte des CSGs a conduit à un changement de paradigme dans le développement des thérapies anticancéreuses, avec la nécessité de cibler dans le traitement non seulement les cellules de la masse tumorale, mais aussi les CSGs. Un criblage différentiel de la chimiothèque Prestwick réalisé au laboratoire a permis d’identifier le bisacodyl comme une molécule présentant une cytotoxicité spécifique sur les CSGs en quiescence.Cette thèse présente un travail sur la caractérisation des CSGs, la compréhension du mode d’action du bisacodyl, ainsi que l’évaluation de son potentiel thérapeutique sur un modèle 3D in intro et des modèles in vivo<br>Glioblastomas are the most malignant primary brain tumors. The identification of glioblastoma stemcells (GSCs) has transformed our comprehension of those tumors by revealing a hierarchical organization. GSCs can self-renew, differentiate and enter into a quiescent state. They are considered as cells which fuel and as the main culprits of tumor relapse. The discovery of GSCs triggered a change in paradigm for cancer therapy. Indeed to gain in efficacy, therapies need to target, not only the cells forming the bulk of the tumor, but also GSCs particularly resistant and endowed with a high tumorigenic potential. Chemical screening of the Prestwick chemical library in our laboratory, unveiled bisacodyl with a specific activity on quiescent GSCs.This thesis presents work on the characterization of GSCs, study of the mode of action of bisacodyl on GSCs, as well as a preclinical evaluation of bisacodyl on a 3D model in vitro and animal models in vivo
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Sadiq, Barzan A. "A dissection of class I phosphoinositide 3-kinase signalling in mouse embryonic fibroblasts and prostate organoids." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/278056.
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Class I PI3Ks are a family (α, β, δ and γ) of ubiquitous lipid kinases that can be activated by cell surface receptors to 3-phosphorylate PI(4,5)P2 (phosphatidylinositol(4,5)-bisphosphate) and generate the signalling lipid PI(3,4,5)P3. The PI(3,4,5)P3 signal then activates a diverse collection of effector proteins involved in regulation of cell migration, metabolism and growth. The importance of this network is evidenced by the relatively high frequency with which cancers acquire gain-of-function mutations in this pathway and huge efforts to make PI3K inhibitors to treat cancer. The canonical model describing these events suggests class I PI3Ks are activated at the plasma membrane and generate PI(3,4,5)P3 in the inner leaflet of the plasma membrane where its effectors are activated. The PI(3,4,5)P3 signal can be terminated directly, by the tumour-suppressor and PI(3,4,5)P3-3-phosphatase PTEN, or modified to a distinct PI(3,4)P2 signal, by SHIP-family 5-phosphatases. The PI(3,4)P2 is removed by INPP4-family 4-phosphatases. Published work has shown that PI(3,4,5)P3 signalling can also occur in endosomes and nuclei, however, there is very little data defining the intracellular distribution of endogenous class I PI3Ks that supports these ideas; this is as a result of technical problems such as; their very low abundance, poor antibody-based tools and artefacts generated by overexpression of PI3Ks. Past work has indicated that, in PTEN-null mouse models of prostate tumour progression, either PI3Kβ or PI3Ks α and β, have important roles. Furthermore, the cell types and mechanism involved remained unclear. Recent published work in the host laboratory had indicated that there is an unexpectedly large accumulation of PI(3,4)P2 in PTEN-null cells that might be an important part of its status as a major tumour suppressor. The explanation and prevalence of this observation was unclear but potentially a result of PTEN also acting as a PI(3,4)P2 3-phosphatase in vivo. MEFs were derived from genetically-modified mice expressing endogenous, AviTagged class I PI3K subunits and used in experiments to define the subcellular localisation of class I PI3Ks. We found that following stimulation with PDGF, class IA PI3K subunits were unexpectedly depleted from the adherent basal membrane, in contrast, p85α and p110α, but not p85β and p110β, accumulated transiently in the nucleus. Interestingly, p110β, but none of the other subunits, was constitutively localised in the nucleus. These results support the idea that class I PI3K and PI(3,4,5)P3 signalling occurs in the nucleus. In organoids derived from WT, PI3Kγ-null or PTEN-null mouse prostate, application of PI3K-selective inhibitors revealed that PI3Kα had a dominant role in generating PI(3,4,5)P3 in prostate epithelial cells. The levels of PI(3,4)P2 were also elevated substantially in PTEN-null, compared to WT prostate organoids, use of PI3K-selective inhibitors suggested that it was also generated by PI3Kα. These data were consistent with the idea that PTEN can act as a PI(3,4)P2 3-phosphatase. Surprisingly, raising the pH of the organoids medium dramatically increased accumulation of PI(3,4,5)P3 and PI(3,4)P2, although the cause of this effect was unclear, we hypothesised the pH of the local environment may influence signalling via class I PI3Ks.
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Tang, Ching-Chun, and 湯景鈞. "Study on Acidic Tumor Microenvironment in Oral Cancer." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/m37yv5.
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碩士<br>國立臺灣大學<br>口腔生物科學研究所<br>107<br>The microenvironment of cancer cells is considered to be an important indicator of cancer progression. Studies have shown that due to the specific metabolic mechanisms of cancer cells, the extracellular matrix of cell has a higher hydrogen ion concentration than the cytoplasm. Exposure of cancer cells to this environment has an effect on their function, including changing in the metabolic system, mediating the growth processes, and expression of autophagy proteins. Compared with cancer within other parts of the body, the oral cavity is the only access to the digestive system. The cancer cells that grow in are more frequently affected by the external environment, especially with acidic environment due to food digestion of secreting seliva. Therefore, Oral cancer cells are not only influenced by endogenous micro-acidification, but also by the exogenous oral digestive system, we presumed that oral cancer should have higher research value in related field about how the microenvironment acidosis changing cell performance. However, there are few related studies using oral cancer as a subject.
In this thesis, the influence of the slightly acidic environment on the growth of cancer cells is taken as the main story. We collaboration in vivo and in vitro experiment. Observing the performance of stemness and extented to drug resistance, proofing that both in vivo and in vitro test can show consistent results.
The results show that acidification has significant impact on different types of oral cancer cells line. For tongue cancer (SAS), long-term acid stimulation its ability to upregulate stemness and further have its influence on proliferation and chemoresistance, at the meanwhile acidosis cancer cell can also improve its vasculogenic mimicry ability. But the acidosis stimulation has totally different influence on oral squamous cell carcinoma (OECM1), stemness of the OEMC1 was down regulation after acid treated but proliferation and chemoresistance ability was same as SAS. Nevertheless, OECM1 in vivo tumor incident rate showed dramatic different from in vitro side population data that OECM1 had much more lower tumor incident rate than SAS. Leak of vasculogenic mimicry ability may be one of the reason that tumor couldn’t form enough vascular-like tube to gain nutrient and lead awful in vivo tumor incident rate.
Books on the topic "Acidic tumor microenvironment"
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Goode, Jamie A., and Derek J. Chadwick, eds. The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity. John Wiley & Sons, Ltd, 2001. http://dx.doi.org/10.1002/0470868716.
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Jamie, Goode, Chadwick Derek, Novartis Foundation, and Symposium on the Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity (2000 : London, England), eds. The tumour microenvironment: Causes and consequences of hypoxia and acidity. Wiley, 2001.
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Goode, Jamie A., Derek J. Chadwick, and Novartis Foundation Symposium Staff. Tumour Microenvironment No. 240: Causes and Consequences of Hypoxia and Acidity. Wiley & Sons, Incorporated, John, 2008.
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Boyer, Michael Joseph. Tumor acidity and the influence of microenvironment on the regulation of intracellular pH: implications for therapy. 1993.
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The Tumour Microenvironment - No. 240: Causes and Consequences of Hypoxia and Acidity (Novartis Foundation Symposia). Wiley, 2001.
Find full textBook chapters on the topic "Acidic tumor microenvironment"
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Ye, Zhizhou, and Donald E. Ayer. "Response to Acidity: The MondoA–TXNIP Checkpoint Couples the Acidic Tumor Microenvironment to Cell Metabolism." In Molecular Genetics of Dysregulated pH Homeostasis. Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1683-2_5.
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Riemann, Anne, M. Rauschner, M. Gießelmann, S. Reime, and O. Thews. "The Acidic Tumor Microenvironment Affects Epithelial-Mesenchymal Transition Markers as Well as Adhesion of NCI-H358 Lung Cancer Cells." In Advances in Experimental Medicine and Biology. Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-48238-1_28.
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Brix, Nikko, and Kirsten Lauber. "Immune Checkpoint Inhibition and Radiotherapy in Head and Neck Squamous Cell Carcinoma: Synergisms and Resistance Mechanisms." In Critical Issues in Head and Neck Oncology. Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-23175-9_2.
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AbstractImmune checkpoint inhibition has emerged as an integral part of the standard-of-care for head and neck squamous cell carcinoma (HNSCC) in recurrent and/or metastatic stages. Clinical responses are impressive but remain limited to a minority of patients. Primary resistance of never-responders is considered to derive from host- and tumor-specific characteristics, the latter comprising tumor immune checkpoint activity, immune contexture, tumor mutational burden, neo-antigen load, and others. Secondary resistance of initially responding patients in addition, appears to be driven predominantly by irreversible T-cell exhaustion and therapy-induced selection of tumor cell clones with mutations in critical genes involved in the response to immune checkpoint inhibition. With particular focus on primary resistance against immune checkpoint inhibition, scientific interest of preclinical and clinical researchers currently aims at the development and evaluation of combined modality treatment approaches. Radiotherapy is a highly promising partner in this regard and represents a crucial treatment modality for patients with locally advanced HNSCC. Historically established as cytotoxic anti-cancer treatment, a growing body of evidence has shown additional locoregional and systemic immunomodulatory effects of radiotherapy. These are largely attributed to reprogramming of the tumor microenvironment driven by dying and senescent irradiated tumor and normal tissue cells and the concomitant cascade of danger signals, chemokines, and cytokines which stimulate immune cell recruitment and activation. Moreover, the irradiated state of tumor cells bears interesting analogy to the anti-viral state, since fragments of nuclear and mitochondrial DNA that are released into the cytosol can stimulate cytosolic nucleic acid sensors to produce intra-tumoral type I interferons which are essential to (re-)activate the cancer immunity cycle and (re-)invigorate systemic anti-tumor T-cell responses. Apart from these tumor adjuvanticity enhancing effects, several reports have also described increased tumor antigenicity upon radiotherapy originating from radiation-induced exposure of neo-antigens. Collectively, radiotherapy thus may serve as a means of personalized in situ vaccination which can synergize with immune checkpoint inhibition and may help to undermine primary resistance. First clinical experiences have shown that scheduling and dosing of such combined modality treatment regimens are challenging. Moreover, recent preclinical evidence suggests that particularly the role of radiation-induced cytokines and interferons appears to be complex in such combined modality settings due to their ambiguous effects on tumor and immune cells in the tumor microenvironment. The signaling cascades that orchestrate immune cell (re-)activation and cell fate decisions in irradiated tumor cells, including tumor cell survival, proliferation, and/or metastasis formation, are intimately interconnected and require further in-depth investigation.
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Jung, Jin G., and Anne Le. "Targeting Metabolic Cross Talk Between Cancer Cells and Cancer-Associated Fibroblasts." In The Heterogeneity of Cancer Metabolism. Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-65768-0_15.
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AbstractAlthough cancer has classically been regarded as a genetic disease of uncontrolled cell growth, the importance of the tumor microenvironment (TME) [1, 2] is continuously emphasized by the accumulating evidence that cancer growth is not simply dependent on the cancer cells themselves [3, 4] but also dependent on angiogenesis [5–8], inflammation [9, 10], and the supporting roles of cancer-associated fibroblasts (CAFs) [11–13]. After the discovery that CAFs are able to remodel the tumor matrix within the TME and provide the nutrients and chemicals to promote cancer cell growth [14], many studies have aimed to uncover the cross talk between cancer cells and CAFs. Moreover, a new paradigm in cancer metabolism shows how cancer cells act like “metabolic parasites” to take up the high-energy metabolites, such as lactate, ketone bodies, free fatty acids, and glutamine from supporting cells, including CAFs and cancer-associated adipocytes (CAAs) [15, 16]. This chapter provides an overview of the metabolic coupling between CAFs and cancer cells to further define the therapeutic options to disrupt the CAF-cancer cell interactions.
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Bossi, Paolo, and Erika Stucchi. "Treatment of OPMD and First Results of Immune Checkpoint Inhibitors." In Critical Issues in Head and Neck Oncology. Springer Nature Switzerland, 2025. https://doi.org/10.1007/978-3-031-84539-0_3.
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Abstract Oral potentially malignant diseases (OPMDs) are a group of oral mucosal lesions that have a higher chance of turning into cancer. They show up in different ways, have different causes, and look differently on a microscopic level. To date, there are no clinical or histological factors that could predict the OPMDs’ malignant transformation to oral squamous cell carcinoma (OSCC), except for previous OSCC and WHO classification. Early diagnosis appears to be essential in these lesions in order to identify the risk of malignant progression and treat them accordingly. The standard treatment for an oral precancerous lesion is surgical resection, which aims to remove all the affected epithelium. Despite the complete surgical removal of the lesion, there is a high probability of recurrence and the development of malignant transformation or a second tumor, based on the theory of “field of cancerization”. Researchers have developed the concept of chemoprevention, which involves using a systemic agent to halt the carcinogenesis process, in an attempt to minimize the probability of recurrence. Researchers have conducted several unsuccessful studies analysing retinoic acid, beta-carotene, vitamin C, the OX-containing oral rinse, and erlotinib. Following these negative results, we conducted a deeper analysis to investigate the peri- and intratumoral immune activity. Studies have demonstrated that changes in the number of tumor infiltrating CD8+, CD3+, and Th1 cells can influence the malignant transformation of OPMDs. Researchers also demonstrated high expression of PD-L1 in those premalignant lesions that progress to cancer. So, an imbalance in the immunosuppressive microenvironment could be the key to turning a premalignant cell into a cancerous cell, which suggests that immunotherapy could be useful as a drug for prevention. Glenn J. Hanna et al. conducted the first study to investigate the effectiveness of immune checkpoint inhibitors in this setting, treating 33 patients with proliferative verrucous leukoplakia with 4 cycles of nivolumab. They showed different levels of lesion regression depending on the size and degree of dysplasia in response to treatment. However, 27% of patients who received nivolumab went on to develop invasive oral cancer, with a 73% cancer-free survival rate after 2 years. Currently, another phase II study, called “IMPEDE trial”, is ongoing that aims to analyse the role of avelumab against malignant transformation in patients with oral premalignant lesions which have any grade of dysplasia and are positive for loss of heterozygosity (LOH). Although these early results on the use of immune checkpoint inhibitors to reverse the malignant transformation of OPDMs are promising, there are many open questions still to be clarified. Fundamental is the need to have randomized trials with long-term outcomes.
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Jin, Cheng, You-Yi Liu, and Bo-Shi Wang. "Mechanisms of Hepatocarcinogenesis Development in an Acidic Microenvironment." In Liver Cancer - Genesis, Progression and Metastasis [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108559.
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Liver cancer represents one of the most common solid tumors globally. Despite curative improvements made in liver cancer therapy these years, the 5-year survival rate of liver cancer remains poor. Understanding the mechanisms involved in the initiation and progression of liver cancer is essential for optimizing therapeutic strategies. In recent years, it has been discovered that the acidic tumor microenvironment attributed to increased glycolysis, and hypoxia contributes to liver cancer progression through promoting cancer cell proliferation, metabolic adaptation, and migration and invasion. In this paper, research advances in the mechanisms of hepatocarcinogenesis development under an acidic microenvironment are reviewed.
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Huang, Zhixian, and Yunchun Zhao. "Application Research of Cloud Computing and Intelligent Manufacturing in Anti-Tumor Responsive Drug Carriers." In Advances in Transdisciplinary Engineering. IOS Press, 2025. https://doi.org/10.3233/atde241377.
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In order to improve the precise delivery of anti-tumor drugs, intelligent manufacturing and cloud computing technologies are adopted to design and optimize responsive drug carriers. Through the specific response of the tumor microenvironment (acidity, temperature, enzymes, etc.), controlled release and targeted delivery of drugs are achieved. The results showed that the pH responsive carrier achieved a drug release rate of 85% in acidic tumor environments, while the intracellular drug release of the enzyme responsive carrier was 65 μ g/mg. PEGylation modification effectively prolonged the in vivo circulation time of the carrier, and combined with combination therapy, the tumor inhibition rate could be increased to 90%.
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"Fluorescence Nanoprobe Imaging Tumor by Sensing the Acidic Microenvironment." In Nanomedicine and Cancer. CRC Press, 2011. http://dx.doi.org/10.1201/b11516-11.
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Hermanus Johannes Sliepen, Sonny. "Bone Cancer Pain, Mechanism and Treatment." In Recent Advances in Bone Tumours and Osteoarthritis. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95910.
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The world health organization (WHO) has predicted a global amount of 19 million cancer cases by 2025. Breast, prostate and lung cancer are common cancer types and show metastasis in 60 to 84% of the cases, with 75 to 90% experiencing life-altering cancer-induced bone pain (CIBP), characterized by continuous, dull progressive pain with movement-induced incident peaks and random breakthrough spikes. Therefore, it is the most difficult pain condition to treat. CIBP is a unique type of pain with neuropathic and nociceptive components. Briefly, an invading tumor cell disturbs the healthy balance of the bone resulting in an acidic microenvironment, activating sensory fibers in the bone. The invaded tumor cell and adjacent stromal cells secrete mediators initiating an immune response with transcriptional signaling, resulting in increased cytokines and growth factors. Sensory nerve fibers are damaged and start to sprout, causing ectopic firing, and as tumors grow in size they activate mechanoreceptors. Aside from bisphosphonates and antibody therapy, CIBP is treated by a range of NSAIDs to strong opioids, but remains undertreated in one-third of cases. This chapter discusses the accompanying CIBP of bone tumors, the mechanism of action and current treatments.
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Turk, Seyhan. "The Impact of Biochemical Alterations in the Tumor Microenvironment on Cancer Progression and Treatment." In Current Researches in Health Sciences-II. Özgür Yayınları, 2023. http://dx.doi.org/10.58830/ozgur.pub128.c626.
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The tumor microenvironment (TME) plays a critical role in cancer progression and treatment response. Recent studies have revealed that biochemical alterations within the TME can significantly influence tumor behavior and therapeutic outcomes.
 Alterations in the TME, such as changes in pH, hypoxia, and nutrient availability, have been shown to promote cancer cell survival and growth. Acidic pH conditions within the TME enhance tumor invasiveness and metastasis while conferring resistance to conventional therapies. Hypoxia, caused by insufficient oxygen supply, not only promotes genetic instability and immune evasion but also induces resistance to radiation and certain chemotherapeutic agents. Additionally, nutrient deprivation within the TME can activate survival pathways in cancer cells, leading to treatment resistance.
 Understanding the biochemical alterations in the TME has led to the development of novel therapeutic approaches. Strategies to modulate the TME, such as targeting angiogenesis, reversing immunosuppression, and normalizing the microenvironment, have shown promise in preclinical and clinical studies. Combining conventional therapies with agents targeting the TME holds potential to overcome treatment resistance and improve patient outcomes.
 In conclusion, the biochemical alterations within the TME significantly impact cancer progression and treatment response. Recognizing these alterations and their influence on therapeutic outcomes is crucial for developing effective treatment strategies. Continued research in this area is vital to unravel the complexity of the TME and identify novel therapeutic targets for improving cancer patient outcomes.
Conference papers on the topic "Acidic tumor microenvironment"
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Lekić, Milica, Mohammad Zoofaghari, Mladen Veletić, and Ilangko Balasingham. "Extracellular vesicle propagation in acidic tumor microenvironment." In NANOCOM '22: The Ninth Annual ACM International Conference on Nanoscale Computing and Communication. ACM, 2022. http://dx.doi.org/10.1145/3558583.3558843.
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Larijani, Nazanin Rohani, Traian Sulea, Mehdi Arbabi Ghahroudi, et al. "Abstract PO-049: Exploiting tumor acidic microenvironment for improved therapeutics." In Abstracts: AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; September 17-18, 2020. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.tumhet2020-po-049.
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Paralkar, Vishwas, Robert J. Aiello, Dan Marshall, et al. "Abstract 2981: Targeting solid tumor acidic microenvironment with an alphalex PARP inhibitor." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2981.
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Ding, Xinliang, Jason Miller, Ashley Campbell, Jonathan Almazan, Stephen Gutowski, and Tian Zhao. "Abstract 2867: Delivery of immunomodulators to the acidic tumor microenvironment by ultra-pH sensitive nanoparticle technology." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-2867.
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Krewson, Elizabeth A., Li V. Yang, and Lixue Dong. "Abstract 1993: Acidic tumor microenvironment stimulation of GPR4 alters cytoskeletal dynamics and migration of vascular endothelial cells." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1993.
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Samykutty, Abhilash, Molly W. McNally, William E. Grizzle, Akiko Chiba, Alexandra Thomas, and Lacey R. McNally. "Abstract 4122: Acidic tumor microenvironment targeted wormhole-shaped mesoporous silica nanoparticles to detect ovarian cancer by multispectral optoacoustic tomography." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-4122.
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Chen, Chong, Lipeng Bai, Fengqi Cao, et al. "Abstract 3546: LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-3546.
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Brück, J., B. Klasen, N. Bausbacher, et al. "Strategies for PET Imaging in Acidic Tumor Microenvironments." In 61. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin. Georg Thieme Verlag, 2023. http://dx.doi.org/10.1055/s-0043-1766343.
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Popova, V. K., and E. V. Dmitrienko. "CALCIUM CARBONATE MATRICES FOR CONTROLLED DELIVERY OF NUCLEIC ACIDS AND THERAPEUTIC AGENTS." In XI МЕЖДУНАРОДНАЯ КОНФЕРЕНЦИЯ МОЛОДЫХ УЧЕНЫХ: БИОИНФОРМАТИКОВ, БИОТЕХНОЛОГОВ, БИОФИЗИКОВ, ВИРУСОЛОГОВ, МОЛЕКУЛЯРНЫХ БИОЛОГОВ И СПЕЦИАЛИСТОВ ФУНДАМЕНТАЛЬНОЙ МЕДИЦИНЫ. IPC NSU, 2024. https://doi.org/10.25205/978-5-4437-1691-6-341.
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If nanosized calcium carbonate is obtained the pH-dependent degradation profile of such compounds makes them promising candidates for selective drug delivery into the tumor microenvironment. Stable suspensions of calcium carbonate nanoparticles and their magnetic composites were obtained. The absence of toxicity of the compounds was proved, as well as their promising potential as transporters of small drug molecules and oligonucleotides.
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Wojtkowiak, Jonathan W., Natalie M. Barkey, Virendra Kumar, Mark C. Lloyd, Robert A. Gatenby, and Robert J. Gillies. "Abstract 1254: Altered lipid and glucose metabolism is a cellular adaptation to tumor acidic microenvironments." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-1254.
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