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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.
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Xu, Jingyong, Yao Li, Zhe Li, Weiwei Shao, Jinghai Song, and Junmin Wei. "Acidic Tumor Microenvironment Promotes Pancreatic Cancer through miR-451a/MEF2D Axis." Journal of Oncology 2022 (January 12, 2022): 1–12. http://dx.doi.org/10.1155/2022/3966386.
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Pancreatic cancer (PC), as a highly malignant and aggressive solid tumor, is common in the digestive system. The acidic microenvironment is one of the critical markers of cancer. Nonetheless, there are few studies on how the acidic microenvironment affects the development of PC. This study focused on investigating the specific molecular mechanisms of the acidic microenvironment in PC. In our study, qRT-PCR was conducted for examining microRNA (miR)-451a and myocyte enhancer factor 2D (MEF2D) expressions in PANC-1 cells. Then, detailed functional effects of an acidic environment on miR-451a and MEF2D in PANC-1 cells were detected by CCK-8, colony formation, flow cytometry, wound healing, transwell, mitochondrial functionality measurement, JC-1 staining, DCFH-DA staining, and sphere formation assays. The relationship between miR-451a and MEF2D was confirmed by luciferase reporter analysis. Under acidic conditions, the increase of proliferation, migration, and invasion of PANC-1 cells was observed. Moreover, the mitochondrial oxidative respiration-related gene miR-451a was reduced in acidic conditions. In addition, we found that, in PANC-1 cells under an acidic environment, miR-451a overexpression enhanced oxygen consumption, mitochondrial membrane potential (MMP) loss, and ROS generation and inhibited proliferation, migration, invasion, and stemness via sponging MEF2D. In a word, our results revealed that the acidic microenvironment regulated PC progression by affecting the miR-451a/MEF2D axis, indicating a novel avenue for the future treatment of PC.
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Noack, Anne-Kathrin, Henrike Lucas, Petr Chytil, Tomáš Etrych, Karsten Mäder, and Thomas Mueller. "Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment." International Journal of Molecular Sciences 21, no. 17 (2020): 6029. http://dx.doi.org/10.3390/ijms21176029.
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Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates.
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Chen, Chong, Peishan Hu, and Yufeng Chen. "Abstract 1356: The lactylation of SLC26A3 in acidic micro-environment contributes to colorectal carcinoma malignant progression." Cancer Research 85, no. 8_Supplement_1 (2025): 1356. https://doi.org/10.1158/1538-7445.am2025-1356.
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A recently discovered post-translational modification, lactylation, can regulate the structure and function of proteins, influencing cellular functions and disease progression. However, its role in tumor progression remains unclear.This study explored the contribution of lactylation modification of solute carrier family 26 member 3 (SLC26A3) in acidic microenvironments to the malignant progression of colorectal carcinoma (CRC). The findings revealed that the acidic tumor microenvironment reduced the stability and expression of SLC26A3 by promoting its lactylation. co-IP experiment results showed SLC26A3 interacted with RNA-binding proteins HuR and CUGBP1, and when the expression of SLC26A3 was decreased, its binding capacity to HuR/CUGBP1 was weakened. This led to an increased interaction of HuR and CUGBP1 with a subset of oncogenic mRNAs, regulating their stability and expression, ultimately promoting the progression of malignant tumors. The study also indicated that the expression of SLC26A3 was negatively correlated with the expression of tumor stem cell markers, and low expression of SLC26A3 promoted the stemness of CRC cells. Furthermore, the expression of SLC26A3 affected the resistance to oxaliplatin (OXA), invasiveness, and migratory ability of CRC cells. In animal models, normalizing the tumor acidic microenvironment and inducing the expression of SLC26A3 inhibited the development of CRC.These findings highlight the role of SLC26A3 as a potential suppressor of CRC recurrence, drug resistance, and metastasis, providing new insights for improving the clinical treatment and prognosis of CRC. Citation Format: Chong Chen, Peishan Hu, Yufeng Chen. The lactylation of SLC26A3 in acidic micro-environment contributes to colorectal carcinoma malignant progression [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 1356.
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Mbugua, Simon Ngigi. "Targeting Tumor Microenvironment by Metal Peroxide Nanoparticles in Cancer Therapy." Bioinorganic Chemistry and Applications 2022 (December 16, 2022): 1–20. http://dx.doi.org/10.1155/2022/5041399.
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Solid tumors have a unique tumor microenvironment (TME), which includes hypoxia, low acidity, and high hydrogen peroxide and glutathione (GSH) levels, among others. These unique factors, which offer favourable microenvironments and nourishment for tumor development and spread, also serve as a gateway for specific and successful cancer therapies. A good example is metal peroxide structures which have been synthesized and utilized to enhance oxygen supply and they have shown great promise in the alleviation of hypoxia. In a hypoxic environment, certain oxygen-dependent treatments such as photodynamic therapy and radiotherapy fail to respond and therefore modulating the hypoxic tumor microenvironment has been found to enhance the antitumor impact of certain drugs. Under acidic environments, the hydrogen peroxide produced by the reaction of metal peroxides with water not only induces oxidative stress but also produces additional oxygen. This is achieved since hydrogen peroxide acts as a reactive substrate for molecules such as catalyse enzymes, alleviating tumor hypoxia observed in the tumor microenvironment. Metal ions released in the process can also offer distinct bioactivity in their own right. Metal peroxides used in anticancer therapy are a rapidly evolving field, and there is good evidence that they are a good option for regulating the tumor microenvironment in cancer therapy. In this regard, the synthesis and mechanisms behind the successful application of metal peroxides to specifically target the tumor microenvironment are highlighted in this review. Various characteristics of TME such as angiogenesis, inflammation, hypoxia, acidity levels, and metal ion homeostasis are addressed in this regard, together with certain forms of synergistic combination treatments.
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Vernucci, Enza, Jaime Abrego, Venugopal Gunda, et al. "Metabolic Alterations in Pancreatic Cancer Progression." Cancers 12, no. 1 (2019): 2. http://dx.doi.org/10.3390/cancers12010002.
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Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.
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Wu, Xiaomin, Boshi Wang, Yingjian Hou, et al. "PFKM-Mediated Glycolysis: A Pathway for ASIC1 to Enhance Cell Survival in the Acidic Microenvironment of Liver Cancer." Biomolecules 15, no. 3 (2025): 356. https://doi.org/10.3390/biom15030356.
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The acidic tumor microenvironment plays a critical role in promoting liver cancer cell survival by enhancing glycolysis and adaptive mechanisms. Acid-sensing ion channel 1 (ASIC1) is a key regulator of pH sensing, but its role in liver cancer progression and underlying mechanisms remain unclear. In this study, we examined ASIC1 expression in clinical liver tumor tissues using immunohistochemistry and immunofluorescence, correlating it with tumor stages. HepG2 and Li-7 cells were cultured in tumor supernatant and acidic conditions to mimic the tumor microenvironment. Western blotting assessed the expression of ASIC1 and glycolysis-related enzymes, with siRNA transfections used to investigate ASIC1 and phosphofructokinase muscle-type (PFKM) in liver cancer cell survival. Our results showed that ASIC1 expression was significantly elevated in liver tumor tissues and correlated with tumor progression. Acidic conditions increased ASIC1 expression in both cell lines, enhancing cell survival, while knockdown of ASIC1 reduced viability and increased apoptosis, particularly under acidic conditions. Moreover, PFKM silencing reversed the survival advantage conferred by ASIC1, confirming PFKM as a critical downstream effector. Additionally, lactate dehydrogenase (LDH) and phosphofructokinase (PFK) activity assays showed no significant changes, suggesting other regulatory mechanisms may also be involved. These findings suggest that the ASIC1/PFKM pathway promotes liver cancer cell survival in acidic environments, representing a potential therapeutic target for disrupting tumor adaptation in liver malignancies.
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Sheng, Liangju, Xuanlei Zhu, Miao Sun, et al. "Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments." Pharmaceuticals 16, no. 2 (2023): 166. http://dx.doi.org/10.3390/ph16020166.
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We prepared a tumor microenvironment-responsive magnetic nanofluid (MNF) for improving tumor targeting, imaging and treatment simultaneously. For this purpose, we synthesized sulfonamide-based amphiphilic copolymers with a suitable pKa at 7.0; then, we utilized them to prepare the tumor microenvironment-responsive MNF by self-assembly of the sulfonamide-based amphiphilic copolymers and hydrophobic monodispersed Fe3O4 nanoparticles at approximately 8 nm. After a series of characterizations, the MNF showed excellent application potential due to the fact of its high stability under physiological conditions and its hypersensitivity toward tumor stroma by forming aggregations within neutral or weak acidic environments. Due to the fact of its tumor microenvironment-responsiveness, the MNF showed great potential for accumulation in tumors, which could enhance MNF-mediated magnetic resonance imaging (MRI), magnetic hyperthermia (MH) and Fenton reaction (FR) in tumor. Moreover, in vitro cell experiment did not only show high biocompatibility of tumor microenvironment-responsive MNF in physiological environment, but also exhibit high efficacy on inhibiting cell proliferation by MH-dependent chemodynamic therapy (CDT), because CDT was triggered and promoted efficiently by MH with increasing strength of alternating magnetic field. Although the current research is limited to in vitro study, these positive results still suggest the great potential of the MNF on effective targeting, diagnosis, and therapy of tumor.
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He, Yongju, Xingyu Fan, Xiaozan Wu, et al. "pH-Responsive size-shrinkable mesoporous silica-based nanocarriers for improving tumor penetration and therapeutic efficacy." Nanoscale 14, no. 4 (2022): 1271–84. http://dx.doi.org/10.1039/d1nr07513f.
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To overcome the nanomedicine penetration barrier across the dense tumor matrix, acidic tumor microenvironment-responsive size-shrinkable mesoporous silica-based nanomedicine is developed for enhancing drug tumor penetration and therapeutic efficacy.
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Zhang, Lingling, Yang Song, Xiaoyan Dai, Wenwen Xu, Mengxia Li та Yuxi Zhu. "Inhibition of IDH3α Enhanced the Efficacy of Chemoimmunotherapy by Regulating Acidic Tumor Microenvironments". Cancers 15, № 6 (2023): 1802. http://dx.doi.org/10.3390/cancers15061802.
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In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial–mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS–STING pathway, promoted CD8+ T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS–STING pathway.
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Dharmaratne, Nayanthara U., Alanna R. Kaplan, and Peter M. Glazer. "Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides." Cells 10, no. 3 (2021): 541. http://dx.doi.org/10.3390/cells10030541.
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The delivery of cancer therapeutics can be limited by pharmacological issues such as poor bioavailability and high toxicity to healthy tissue. pH-low insertion peptides (pHLIPs) represent a promising tool to overcome these limitations. pHLIPs allow for the selective delivery of agents to tumors on the basis of pH, taking advantage of the acidity of the hypoxic tumor microenvironment. This review article highlights the various applications in which pHLIPs have been utilized for targeting and treating diseases in hypoxic environments, including delivery of small molecule inhibitors, toxins, nucleic acid analogs, fluorescent dyes, and nanoparticles.
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Sun, Xiao, Guilong Zhang, and Zhengyan Wu. "Nanostructures for pH-sensitive Drug Delivery and Magnetic Resonance Contrast Enhancement Systems." Current Medicinal Chemistry 25, no. 25 (2018): 3036–57. http://dx.doi.org/10.2174/0929867324666170406110642.
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According to the differences of microenvironments between tumors and healthy tissues, if the anticancer drugs or magnetic resonance contrast agents (MRCAs) can be controlled to precisely match physiological needs at targeted tumor sites, it is expected to acquire better therapeutic efficacy and more accurate diagnosis. Over the decade, stimuli-responsive nanomaterials have been a research hotspot for cancer treatment and diagnosis because they show many excellent functions, such as in vivo imaging, combined targeting drug delivery and systemic controlled release, extended circulation time, etc. Among the various stimuli nanosystems, pH-stimuli mode is regarded as the most general strategy because of solid tumors acidosis. When exposed to weakly acidic tumor microenvironment, pH-responsive nanoplatforms can generate physicochemical changes for their structure and surface characteristics, causing drug release or contrast enhancement. In this review, we focused on the designs of various pH-responsive nanoplatforms and discussed the mechanisms of controlled drug release or switch on-off in MRCAs. This review also discussed the efficacy of cellular internalization for these nanoplatforms via endocytosis of acidic tumor cell. Meanwhile, nanoplatforms response to acidic intracellular pH (such as endosome, lysosome) are discussed, along with approaches for improving drug release performance and magnetic resonance contrast enhancement. A greater understanding of these pH-responsive nanoplatforms will help design more efficient nanomedicine to address the challenges encountered in conventional diagnosis and chemotherapy.
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Wang, Joy X., Stephen Y. C. Choi, Xiaojia Niu, et al. "Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity." International Journal of Molecular Sciences 21, no. 21 (2020): 8363. http://dx.doi.org/10.3390/ijms21218363.
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Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.
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Wojtkowiak, Jonathan W., Daniel Verduzco, Karla J. Schramm, and Robert J. Gillies. "Drug Resistance and Cellular Adaptation to Tumor Acidic pH Microenvironment." Molecular Pharmaceutics 8, no. 6 (2011): 2032–38. http://dx.doi.org/10.1021/mp200292c.
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Bhattacharya, Saswati, Jasmina Khanam, Pradipta Sarkar, and Tapan Kumar Pal. "A chemotherapeutic approach targeting the acidic tumor microenvironment: combination of a proton pump inhibitor and paclitaxel for statistically optimized nanotherapeutics." RSC Advances 9, no. 1 (2019): 240–54. http://dx.doi.org/10.1039/c8ra08924h.
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Higashi, Sadayuki, Munekazu Yamakuchi, Hirohito Hashinokuchi та ін. "Adaptation to acidic conditions that mimic the tumor microenvironment, downregulates miR-193b-3p, and induces EMT via TGFβ2 in A549 cells". PLOS ONE 20, № 2 (2025): e0318811. https://doi.org/10.1371/journal.pone.0318811.
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The acidic tumor microenvironment plays a critical role in the malignant transformation of cancer cells. One mechanism underlying this transformation involves epithelial-mesenchymal transition (EMT). This is induced by prolonged exposure to acidic conditions. EMT is an essential process in cancer progression, with Transforming Growth Factor Beta (TGF-β) playing a central role in its induction. However, little was known about the factors regulating TGF-β under acidic conditions. This study aimed to elucidate the mechanism of EMT under acidic conditions and identify novel therapeutic targets to inhibit cancer cell migration and metastasis. Focusing on lung cancer, we explored microRNAs associated with EMT that were differentially expressed under acidic conditions in A549 cells and identified miR-193b-3p as a novel candidate. Under acidic conditions, miR-193b-3p expression decreased around days 3–14. Downregulation of miR-193b-3p promoted increased TGFβ2 expression, resulting in EMT changes in A549 cells. Our study suggests that the interaction between miR-193b-3p, TGFβ2, and the acidic tumor microenvironment promotes cancer EMT change. Understanding these interactions may not only enhance our biological comprehension of cancer, but also pave the way for the development of targeted therapies to inhibit cancer metastasis.
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Sun, Yu, Zekun Wang, Pu Zhang, et al. "Mesoporous silica integrated with Fe3O4 and palmitoyl ascorbate as a new nano-Fenton reactor for amplified tumor oxidation therapy." Biomaterials Science 8, no. 24 (2020): 7154–65. http://dx.doi.org/10.1039/d0bm01738h.
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Lei, Yanli, Xiaoxiao He, Jinlu Tang, et al. "Ultra-pH-responsive split i-motif based aptamer anchoring strategy for specific activatable imaging of acidic tumor microenvironment." Chemical Communications 54, no. 73 (2018): 10288–91. http://dx.doi.org/10.1039/c8cc04420a.
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Reuss, Anna Maria, Dominik Groos, Michael Buchfelder, and Nicolai Savaskan. "The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma." International Journal of Molecular Sciences 22, no. 11 (2021): 5518. http://dx.doi.org/10.3390/ijms22115518.
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Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.
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Walter, Sebastian Gottfried, Peter Knöll, Peer Eysel, et al. "Molecular In-Depth Characterization of Chondrosarcoma for Current and Future Targeted Therapies." Cancers 15, no. 9 (2023): 2556. http://dx.doi.org/10.3390/cancers15092556.
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Chondrosarcoma (CHS) are heterogenous, but as a whole, represent the second most common primary malignant bone tumor entity. Although knowledge on tumor biology has grown exponentially during the past few decades, surgical resection remains the gold standard for the treatment of these tumors, while radiation and differentiated chemotherapy do not result in sufficient cancer control. An in-depth molecular characterization of CHS reveals significant differences compared to tumors of epithelial origin. Genetically, CHS are heterogenous, but there is no characteristic mutation defining CHS, and yet, IDH1 and IDH2 mutations are frequent. Hypovascularization, extracellular matrix composition of collagen, proteoglycans, and hyaluronan create a mechanical barrier for tumor suppressive immune cells. Comparatively low proliferation rates, MDR-1 expression and an acidic tumor microenvironment further limit therapeutic options in CHS. Future advances in CHS therapy depend on the further characterization of CHS, especially the tumor immune microenvironment, for improved and better targeted therapies.
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Liu, Xiaodong, Qian Chen, Guangbao Yang, et al. "Magnetic nanomaterials with near-infrared pH-activatable fluorescence via iron-catalyzed AGET ATRP for tumor acidic microenvironment imaging." Journal of Materials Chemistry B 3, no. 14 (2015): 2786–800. http://dx.doi.org/10.1039/c5tb00070j.
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This work provides a fluorescent/magnetic iron oxide nanomaterials prototype to visualize the solid tumor in vivo by sensing the tumor acidic microenvironment, and a satisfactory tumor-to-normal tissue signal ratio (T/N ratio) and a prolonged time-window for 4T1 tumor visualization were observed in vivo.
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Wang, Heng, Beilei Wang, Jie Jiang, et al. "SnSe Nanosheets Mimic Lactate Dehydrogenase to Reverse Tumor Acid Microenvironment Metabolism for Enhancement of Tumor Therapy." Molecules 27, no. 23 (2022): 8552. http://dx.doi.org/10.3390/molecules27238552.
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The acidic tumor microenvironment (TME) is unfriendly to the activity and function of immune cells in the TME. Here, we report inorganic nanozymes (i.e., SnSe NSs) that mimic the catalytic activity of lactate dehydrogenase to degrade lactate to pyruvate, contributing to the metabolic treatment of tumors. As found in this study, SnSe NSs successfully decreased lactate levels in cells and tumors, as well as reduced tumor acidity. This is associated with activation of the immune response of T cells, thus alleviating the immunosuppressive environment of the TME. More importantly, the nanozyme successfully inhibited tumor growth in mutilate mouse tumor models. Thus, SnSe NSs show a promising result in lactate depletion and tumor suppression, which exemplifies its potential strategy in targeting lactate for metabolic therapy.
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Xie, Yunong, Stephanie Ma, and Man Tong. "Metabolic Plasticity of Cancer Stem Cells in Response to Microenvironmental Cues." Cancers 14, no. 21 (2022): 5345. http://dx.doi.org/10.3390/cancers14215345.
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An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment.
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Andreucci, Elena, Silvia Peppicelli, Jessica Ruzzolini, et al. "The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells." Journal of Molecular Medicine 98, no. 10 (2020): 1431–46. http://dx.doi.org/10.1007/s00109-020-01959-y.
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Abstract Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both “aerobic” and “anaerobic” glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-to-mesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosis-induced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor. Key messages • Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells • Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells • Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells • Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells • Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells
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Zhan, Yuan, Mara Gonçalves, Panpan Yi, et al. "Thermo/redox/pH-triple sensitive poly(N-isopropylacrylamide-co-acrylic acid) nanogels for anticancer drug delivery." Journal of Materials Chemistry B 3, no. 20 (2015): 4221–30. http://dx.doi.org/10.1039/c5tb00468c.
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Doxorubicin is effectively loaded into disulfide-crosslinked poly(N-isopropylacrylamide-co-acrylic acid) nanogels, which can be triggerably released in a heating or reducing acidic tumor microenvironment.
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Palma, Susana I. C. J., Alexandra R. Fernandes, and Ana C. A. Roque. "An affinity triggered MRI nanoprobe for pH-dependent cell labeling." RSC Advances 6, no. 114 (2016): 113503–12. http://dx.doi.org/10.1039/c6ra17217b.
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The pH-sensitive affinity pair composed by neutravidin and iminobiotin was used to develop a multilayered Magnetic Resonance Imaging (MRI) nanoprobe responsive to the acidic pH of tumor microenvironment.
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Lv, Shuxin, Wei Long, Junchi Chen, et al. "Dual pH-triggered catalytic selective Mn clusters for cancer radiosensitization and radioprotection." Nanoscale 12, no. 2 (2020): 548–57. http://dx.doi.org/10.1039/c9nr08192e.
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Mn clusters with pH-triggered catalytic selective capacity could optimize the effects of radiotherapy in the acidic tumor microenvironment, while protecting normal tissues from radiation in neutral circumstances simultaneously.
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Peppicelli, Silvia, Elena Andreucci, Jessica Ruzzolini, et al. "The acidic microenvironment as a possible niche of dormant tumor cells." Cellular and Molecular Life Sciences 74, no. 15 (2017): 2761–71. http://dx.doi.org/10.1007/s00018-017-2496-y.
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Shen, Ming, Yongzhuo Huang, Limei Han, et al. "Multifunctional drug delivery system for targeting tumor and its acidic microenvironment." Journal of Controlled Release 161, no. 3 (2012): 884–92. http://dx.doi.org/10.1016/j.jconrel.2012.05.013.
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Choi, Joung-Woo, Soo-Jung Jung, Dayananda Kasala, et al. "pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis." Journal of Controlled Release 205 (May 2015): 134–43. http://dx.doi.org/10.1016/j.jconrel.2015.01.005.
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Zhang, Bingyu, Xue Zhang, Xianxin Wen, and Dui Qin. "Construction of a three-dimensional culture system based on Gelatin methacryloyl hydrogel for lung cancer cells." Journal of Physics: Conference Series 2783, no. 1 (2024): 012061. http://dx.doi.org/10.1088/1742-6596/2783/1/012061.
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Abstract Hypoxia and acidity are key characteristics of the tumor microenvironment (TME). Gelatin methacryloyl (GelMA) is a versatile biomaterial extensively utilized in various biomedical fields. Studies have shown that during the photocrosslinking process of GelMA hydrogel, the commonly used photoinitiator Irgacure 2959 consumes oxygen and induces an acidic and hypoxia environment. However, there is currently limited research on its involvement in the three-dimensional (3D) culture of tumor cells. Therefore, we constructed a 3D culture system utilizing GelMA hydrogel and investigated its influence on the growth and drug response of lung cancer cells (A549). The results demonstrated that the GelMA hydrogel-based 3D culture system exhibited excellent biocompatibility and robust mechanical properties and provided an acidic microenvironment conducive to tumor cell proliferation. Furthermore, the cancer cells exhibited heightened sensitivity to chemotherapeutics in this 3D culture model. These results suggest that the GelMA hydrogel-based 3D culture system can serve as a perfect model for in vitro study of tumor cells.
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Voss, Ninna C. S., Thomas Dreyer, Mikkel B. Henningsen, Pernille Vahl, Bent Honoré, and Ebbe Boedtkjer. "Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO3 Therapy in Murine Breast Tissue." Cancers 12, no. 4 (2020): 891. http://dx.doi.org/10.3390/cancers12040891.
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The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO3-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO3 therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO3-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO3 therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO3-treated mice and correlates negatively with breast tumor latency. Oral NaHCO3 therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns—observed by high-throughput proteomics analyses—between cancer and normal breast tissue and in response to oral NaHCO3 therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO3 therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO3 therapy that in breast tissue cancel out previously reported anti-neoplastic effects.
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Clark, Amelia M., and Brian J. Altman. "Circadian control of macrophages in the tumor microenvironment." Journal of Immunology 208, no. 1_Supplement (2022): 165.06. http://dx.doi.org/10.4049/jimmunol.208.supp.165.06.
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Abstract Introduction All leukocytes tested to date have functional circadian clocks, and nearly every arm of the immune response is subject to circadian regulation. Circadian clocks instruct the time-of-day-dependent, rhythmic expression of genes in a tissue- and cell-specific manner. In macrophages (mΦs), the circadian clock regulates several factors that are critical to executing effective immune responses. Tumor-associated mΦs are major contributors to immune suppression in the tumor microenvironment (TME). Evidence suggests that metabolically stressful factors in the TME such as acidic pH and nutrient limitation promote mΦ-mediated immune suppression, and recent data point to dysregulation of the circadian clock downstream of metabolic stress. Methods We study the effect of TME-associated metabolic stress on the circadian clock of mΦs in vitro by culturing bone marrow-derived mΦs in conditions mimicking acidic pH and nutrient limitations that have been observed in the TME. To study the impact of mΦ-intrinsic circadian rhythms on tumorigenesis in vivo, we use mice genetically engineered to have a myeloid cell-specific disruption of the circadian clock via deletion of the key clock protein BMAL1. Results Oscillation of core clock proteins is altered in mΦs subjected to TME-associated metabolic stress. Additionally, we observe increased tumor growth in mice co-injected with mΦs whose circadian clocks were disrupted compared to mice co-injected with mΦs whose circadian clocks were functional. Conclusion Our data suggests that stressful conditions associated with the TME can alter the mΦ circadian clock, and that a functional circadian clock in mΦs can suppress tumor growth in a syngeneic murine tumor model of pancreatic cancer. This research has been supported by the following fellowships and grants: 2021-Current: Wilmot Predoctoral Cancer Research Fellowship, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 2020-2021: NIH T32 Training Grant in Cellular, Biochemical & Molecular Sciences, University of Rochester Medical Center, Rochester, NY
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Si, Zhan, Cuiyun Huang, Xihui Gao, and Cong Li. "pH-responsive near-infrared nanoprobe imaging metastases by sensing acidic microenvironment." RSC Adv. 4, no. 98 (2014): 55548–55. http://dx.doi.org/10.1039/c4ra07984a.
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A pH responsive near-infrared fluorescence nanoprobe was developed and visualized pulmonary metastases in a mouse model with a volume as small as 0.5 mm<sup>3</sup> by sensing the acidic tumor microenvironment.
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Wang, Sheng, Jiaji Mao, Hong Liu, et al. "pH-Sensitive nanotheranostics for dual-modality imaging guided nanoenzyme catalysis therapy and phototherapy." Journal of Materials Chemistry B 8, no. 22 (2020): 4859–69. http://dx.doi.org/10.1039/c9tb02731a.
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A theranostic nanosystem with a pH-sensitive structure showed charge conversion properties in the tumor acidic microenvironment. It could perform dual-modality imaging diagnosis and carry out catalysis therapy and phototherapy.
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Shiba, Hiroya, Misaki Nishio, Mei Sawada, et al. "Carboxy-terminal dendrimers with phenylalanine for a pH-sensitive delivery system into immune cells including T cells." Journal of Materials Chemistry B 10, no. 14 (2022): 2463–70. http://dx.doi.org/10.1039/d1tb01980e.
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Dendrimers with phenylalanine (Phe) and cyclohexanedicarboxylic acid (CHex) showed higher uptake into various cells including T cells via endocytosis. The cell association was enhanced under weak acidic conditions observed in tumor microenvironment.
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Qi, Guohua, Bo Wang, Xiangfu Song, Haijuan Li, and Yongdong Jin. "A green, efficient and precise hydrogen therapy of cancer based on in vivo electrochemistry." National Science Review 7, no. 3 (2019): 660–70. http://dx.doi.org/10.1093/nsr/nwz199.
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Abstract By combined use of traditional Chinese acupuncture Fe needle electrode and in vivo electrochemistry, we achieved in vivo H2 generation in tumors in a controllable manner and exploited it for effective and green therapy of tumors for the first time. The cathodic acupuncture electrodes working under an applied voltage of ∼3 V (with minimal damage to the living body) undergo effective electrochemical reactions in the acidic tumor area that produce sufficient H2 locally to cause cancer cells to burst and die. Due to puncture positioning, the acidic tumor microenvironment and gas diffusion effect, the developed H2 generation electrochemotherapy (H2-ECT) strategy enables precise and large-scale tumor therapy, as demonstrated by in vivo treatment of diseased mice (glioma and breast cancers). Such green H2-ECT is simple, highly efficient and minimally invasive, requiring no expensive medical equipment or nano materials and medication, and is therefore very promising for potential clinical applications.
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Tsai, Ming-Hsien, Cheng-Liang Peng, Cheng-Jung Yao, and Ming-Jium Shieh. "Enhanced efficacy of chemotherapeutic drugs against colorectal cancer using ligand-decorated self-breakable agents." RSC Advances 5, no. 112 (2015): 92361–70. http://dx.doi.org/10.1039/c5ra16175d.
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Targeting self-breakable micelles could facilitate Caco2 cancer cells in acidic tumor microenvironment to take up SN38 which the micelle loaded with and trigger drug release in cancer cells, resulting in enhanced drug efficacy.
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Yoneda, Toshiyuki N/A, Masahiro N/A Hiasa, Yuki N/A Nagata, Matthew S. Ripsch, Fletcher A. White, and G. David Roodman. "Acidic Extracellular Microenvironment in Myeloma-Colonized Bone Contributes to Bone Pain." Blood 124, no. 21 (2014): 3397. http://dx.doi.org/10.1182/blood.v124.21.3397.3397.
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Abstract Multiple myeloma (MM) bone disease results in devastating bone pain and fractures, which are the major cause of morbidity, and contribute to increased mortality and diminish the quality of life in MM patients. Current treatments for MM bone pain do not completely control the pain and have serious side effects. Thus, new therapies are needed to control myeloma bone pain. However, the mechanisms responsible for MM-associated bone pain are poorly understood. Specific osteoclast inhibitors (bisphosphonates and denosumab) can reduce bone pain in MM patients, suggesting that factors released at the tumor-bone interface during osteoclastic bone resorption may be important contributors to bone pain.Bone-resorbing osteoclasts release protons to dissolve bone minerals and aggressively proliferating tumor cells also release protons/lactate as a consequenece of aerobic glycolysis. Since acidosis is algogenic for primary afferent sensory neurons, we reasoned that an acidic extracellular microenvironment created by the release of protons by osteoclasts and MM cells play a critical role in the pathophysiology of bone pain. To investigate the mechanism of bone pain associated with MM, we used an animal model in which the JJN3 human MM cells were inoculated into the tibiae of SCID mice. Control mice received PBS. Bone pain was assessed by determining tactile hypersensitivity and thermal hyperalgesia of JJN3-bearing mice using von Frey and plantar tests. Administration of the pH probe acridine orange to JJN3-bearing mice revealed that resorption pits beneath bone-resorbing osteoclasts and JJN3-colonized tibiae are acidic. Mice bearing JJN3 MM in their tibiae displayed progressive tactile hypersensitivity and thermal hyperalgesia as the tumor grew. Of note, the bisphosphonate zoledronic acid significantly reduced the progression of the tactile hypersensitivity and thermal hyperalgesia, suggesting that these nociceptive behaviors of JJN3-bearing mice are due to osteoclast-mediated bone pain. Importantly, the non-selective proton pump inhibitor bafilomycin A1 inhibited the creation of the acidic extracellular microenvironment in JJN3-colonized bone and significantly prevented the progression of the nociceptive behaviors. These results support that the acidic extracellular microenvironment is responsible for evoking bone pain. Immunohistochemical examination to identify acid-sensing mechanisms present in bone showed that the calcitonin gene-related peptide (CGRP)-positive sensory neurons innervating bone are adjacent to osteoclasts with co-expression of the acid-sensing nociceptor, the transient receptor potential vanilloid subfamily member 1 (TRPV1). To determine the role of TRPV1 in the excitation of sensory neurons, primary sensory neuron cells isolated from dorsal root ganglion (DRG) were exposed to acidic medium (pH 6.5) and examined for intracellular Ca2+ mobilization using Fura 2 AM calcium imaging assays. Acidic medium induced Ca2+ influx in DRG sensory neuron cells and the induced Ca2+ influx was blocked in the presence of the specific TRPV1 antagonist SB366791, while the specific TRPV4 antagonist RN1734 showed no effect. Further, the specific antagonist for the acid-sensing ion channel 3 (ASIC3), APETx2, also blocked the induction of Ca2+ influx. Neutral medium (pH 7.4) did not induce Ca2+ influx. Taken together, these results suggest that TRPV1 and ASIC3 play an important role in the excitation of sensory neurons exposed to acidic extracellular microenvironment. Our results suggest that the acidic extracellular microenvironments created by protons released from osteoclasts and MM cells excite sensory neurons associated with bone via the acid-sensing nociceptors, TRPV1 and ASIC3, to evoke bone pain. TRPV1 and ASIC3 may be potential targets for ameliorating bone pain in MM. Disclosures Roodman: Eli Lilly and Co.: Research Funding.
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Bogdanov, A. A., An A. Bogdanov, and V. M. Moiseyenko. "Alkalinization of the tumor microenvironment: are there prospects as a therapeutic objective?" Practical oncology 23, no. 3 (2022): 143–59. http://dx.doi.org/10.31917/2303143.
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Tumor acidity is one of the hallmarks of cancer. The use of glycolysis as the main source of ATP production due to the metabolic reprogramming of cancer cells makes their intracellular pH alkaline and extracellular pH acidic. This metabolic reprogramming and acidification are part of the general defenses that allow malignant cells to survive, multiply, spread, and become resistant to therapies. Tumor acidity may also be associated with a poor prognosis for cancer patients, and clinicians should consider this when diagnosing and determining optimal treatment. On the other hand, the inversion of the pH gradient in tumors could be a weakness, which will allow the development of new promising therapies. Pharmacological inhibition of pH regulation pathways and alkalinization of the tumor appear to be prospective therapeutic options for cancer treatment. Alkalization therapy does not contradict standard treatment methods and can be used in combination to increase effectiveness. Here, we have tried to summarize the basic knowledge about tumor acidity and related potential cancer treatment options.
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Nam, Jeong-Seok, Choong-Jae Lee, and Hyeon-Ji Yun. "Abstract 5111: Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the acidic tumor microenvironment." Cancer Research 85, no. 8_Supplement_1 (2025): 5111. https://doi.org/10.1158/1538-7445.am2025-5111.
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Abstract The tumor microenvironment (TME) has a significant impact on colorectal cancer (CRC) progression by promoting tumor survival and aggressive behavior. A key player in this process is the tumor-associated glycoprotein dysadherin, which is highly expressed in aggressive CRC cells and facilitates their adaptation to the TME. In this study, we conducted a comprehensive bioinformatics analysis of clinical genomic data from CRC patients, integrated with studies on dysadherin-knockout CRC cells. We also examined the downstream effects of dysadherin in human CRC cells, patient tissue samples, and a xenograft mouse model. Through bioinformatics and pathological analysis, we found that increased tumor acidity is a prominent feature of CRC progression and is positively associated with high dysadherin expression. Overexpression and silencing studies of dysadherin in CRC cells further confirmed that high dysadherin levels enhance malignant traits, especially under acidic conditions within the TME. Mechanistically, dysadherin activates the Integrin/FAK/STAT3 signaling pathway, leading to upregulation of carbonic anhydrase 9 (CA9). CA9 helps cancer cells survive in acidic environments by maintaining intracellular pH balance. By buffering the acidic TME, CA9 enhances CRC cell adaptation and resilience in an otherwise hostile environment. Notably, the deletion of dysadherin in xenograft models led to reduced tumor growth, while the reintroduction of CA9 restored malignancy, underscoring the essential role of the dysadherin/CA9 axis. This pathway is crucial for CRC cell survival in acidic TME, positioning dysadherin and CA9 as promising prognostic markers and therapeutic targets. Targeting this axis could disrupt CRC progression, offering new therapeutic avenues and potentially more effective interventions for inhibiting disease advancement Citation Format: Jeong-Seok Nam, Choong-Jae Lee, Hyeon-Ji Yun. Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the 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 5111.