Acidic tumor microenvironment and pH-sensing G protein-coupled receptors

Justus, Calvin R.; Dong, Lixue; Yang, Li V.

doi:10.3389/fphys.2013.00354

Cited by 284 publications

(271 citation statements)

References 105 publications

(184 reference statements)

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“…At the same time, Gpr132 is also highly sensitive to acidity (13), a hallmark of the cancer milieu. Thus, we hypothesized that Gpr132 might be the macrophage pH sensor that controls macrophage phenotype in response to the acidic tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

“…In solid tumors, TAMs are usually biased toward M2 (9). Due to hypoxia and glycolytic cancer cell metabolism, the tumor environment is usually acidic, which affects tumor progression by acting on both cancer cells and stromal cells, including macrophages (10,13,14). A recent study shows that cancer cell-derived lactate can educate macrophages to functional TAMs, which, in turn, promotes tumor growth (14).…”

mentioning

confidence: 99%

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Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Chen

Zuo

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

310

238

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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.reast cancer is the most frequently diagnosed nonskin type of malignancy, and the second leading cause of cancer-related death in women. The 5-y survival rate is 89% in patients who have primary breast cancer, whereas the medium survival of patients with metastatic breast cancer is only 1-2 y (1, 2). Metastasis is the primary cause of breast cancer-related deaths; however, the molecular mechanisms underlying this process are still poorly understood. It has been well established that the tumor microenvironment plays an important role in breast cancer metastasis (3-6). Tumor-associated macrophages (TAMs) make up the largest population of stromal cells that suppress antitumor immunity and foster tumor progression in mouse models of breast cancer (3,(6)(7)(8). TAMs also promote metastasis and correlate with poor prognosis in patients with breast cancer (7, 9). Conversely, TAM functions are also tightly regulated by tumor cells (10, 11). However, the mechanisms underlying this reciprocal regulation between cancer cells and macrophages during metastasis remain elusive.Macrophages are heterogeneous immune cells that can exhibit distinct functions and phenotypes depending on different microenvironment signals (9, 12). They can be broadly divided into classically activated (M1) and alternatively activated (M2) macrophages, the latter of which generally display promalignancy activity (9, 12). In solid tumors, TAMs are usually biased toward M2 (9). Due to hypoxia and glycolytic cancer cell metabolism, the tumor environment is usually acidic, which affects tumor progression by acting on both cancer cells and stromal cells, including macrophages (10,13,14). A recent study shows that cancer cell-derived lactate can educate macrophages to functional TAMs, which, in turn, promotes tumor growth (14). Nonetheless, how lactate activation of TAMs affects cancer metastasis is poorly understood. Importantly, the molecular basis by which macrophages sense and respond t...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Chen

Zuo

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

310

238

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“…However, even if a sufficient amount of anticancer drugs are delivered to metastatic tumors, not all drugs are effective at killing cancer cells in micrometastatic colonies [13]. Metastatic tumor cells that grow quickly produce a large amount of acidic byproducts, such as lactic acid, during the conversion of glucose into energy [14]. This tissue acidifying process, also known as the Warburg effect, can reduce chemotherapy efficacy, because many anticancer drugs lose activity in acidic conditions [15,16].…”

Section: Methods and Resultsmentioning

confidence: 99%

Polymer Nanoassemblies With solvato- and halo-fluorochromism for Drug Release Monitoring and Metastasis Imaging

2015

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Background: Theranostics, an emerging technique that combines therapeutic and diagnostic modalities for various diseases, holds promise to detect cancer in early stages, eradicate metastatic tumors and ultimately reduce cancer mortality. Methods & results:This study reports unique polymer nanoassemblies that increase fluorescence intensity upon addition of hydrophobic drugs and either increase or decrease fluorescence intensity in acidic environments, depending on nanoparticle core environment properties. Extensive spectroscopic analyses were performed to determine optimal excitation and emission wavelengths, which enabled real time measurement of drugs releasing from the nanoassemblies and ex vivo imaging of acidic liver metastatic tumors from mice. Conclusion: Polymer nanoassemblies with solvato-and halo-fluorochromic properties are promising platforms to develop novel theranostic tools for the detection and treatment of metastatic tumors.

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“…Hypoxia, acidosis, inflammation, defective vasculature, poor blood perfusion, and deregulated cancer cell metabolism are hallmarks of the tumor microenvironment. [91][92][93] The acidity …”

Section: Role For the Ph-sensing Gpcrs In Tumor Biologymentioning

confidence: 99%

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

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Acidic tumor microenvironment and pH-sensing G protein-coupled receptors

Cited by 284 publications

References 105 publications

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Polymer Nanoassemblies With solvato- and halo-fluorochromism for Drug Release Monitoring and Metastasis Imaging

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

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