CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis
Tóm tắt
In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism. Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites. We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5−/− cells, that exhibit reduced glycolytic metabolism. These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.
Tài liệu tham khảo
Diers AR, Broniowska KA, Chang C-F, Hogg N. Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J. 2012;444:561–71.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.
Zu XL, Guppy M. Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun. 2004;313(3):459–65.
Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64(11):3892–9.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–7.
Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27(1):441–64.
Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.
Biswas S, Sengupta S, Roy Chowdhury S, et al. CXCL13–CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. Breast Cancer Res Treat. 2014;143(2):265–76.
See ALP, Chong PK, Lu S-Y, Lim YP. CXCL3 is a potential target for breast cancer metastasis. Curr Cancer Drug Targets. 2014;14(3):294–309.
Luboshits G, Shina S, Kaplan O, et al. Elevated expression of the CC chemokine Regulated On Activation, Normal T Cell Expressed and Secreted (RANTES) in advanced breast carcinoma. Cancer Res. 1999;59:4681–7.
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557–63.
Khalid A, Wolfram J, Ferrari I, et al. Recent advances in discovering the role of CCL5 in metastatic breast cancer. Mini Rev Med Chem. 2015;15(13):1063–72.
Lv D, Zhang Y, Kim HJ, et al. CCL5 as a potential immunotherapeutic target in triple-negative breast cancer. Cell Mol Immunol. 2013;10(4):303–10.
Yaal-Hahoshen N, Shina S, Leider-Trejo L, et al. The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients. Clin Cancer Res. 2006;12(15):4474–80.
Niwa Y, Akamatsu H, Niwa H, et al. Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin Cancer Res. 2001;7(February):285–9.
Zhang Q, Qin J, Zhong L, et al. CCL5-mediated Th2 immune polarization promotes metastasis in luminal breast cancer. Cancer Res. 2015;75(20):4312–21.
Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125(9):3365–76.
Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86(November):1065–73.
Murooka TT, Rahbar R, Fish EN. CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation. Biochem Biophys Res Commun. 2009;387(2):381–6.
Gao D, Rahbar R, Fish EN. CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells. Open Biol. 2016;6(6):3831–52.
Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992;12(3):954–61.
Lin EY, Jones JG, Li P, et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003;163(5):2113–26.
Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer. 2017;24(1):3–15.
Shultz LD, Lyons BL, Burzenski LM, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174:6477–89.
Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207.
Velasco-Velázquez M, Jiao X, De La Fuente M, et al. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012;72(15):3839–50.
Azenshtein E, Luboshits G, Shina S, et al. The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity. Cancer Res. 2002;62(4):1093–102.
Cornett DS, Frappier SL, Caprioli RM. MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem. 2008;80(14):5648–53.
Gessel MM, Norris JL, Caprioli RM. MALDI imaging mass spectrometry: spatial molecular analysis to enable a new age of discovery. J Proteome. 2014;107:71–82.
Dekker TJA, Jones EA, Corver WE, et al. Towards imaging metabolic pathways in tissues. Anal Bioanal Chem. 2015;407(8):2167–76.
Smith CA, O’Maille G, Want EJ, et al. METLIN: a metabolite mass spectral database. Ther Drug Monit. 2005;27(6):747–51.
Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG et al. Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol. 2017; Jan;14(1):11-31.
Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.
Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways. Science. 2001;292(5516):504–7.
Quail D, Joyce J. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–37.
Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000;248(3):171–83.
Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006;79(3–4):123–30.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.
Simoes RV, Serganova IS, Kruchevsky N, et al. Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment. Neoplasia. 2015;17(8):671–84.
Roy A, Bera S. CAF cellular glycolysis: linking cancer cells with the microenvironment. Tumor Biol. 2016;37(7):8503–14.
Mezawa Y, Orimo A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res. 2016;365(3):675–89.
Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30(9):1002–19.
Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008;267(2):271–85.
Zhang Y, Yao F, Yao X, et al. Role of CCL5 in invasion, proliferation and proportion of CD44+/CD24- phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression. Oncol Rep. 2009;21(4):1113–21.
Robinson SC, Scott KA, Wilson JL, et al. A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res. 2003;63(23):8360–5.
Velasco-Velázquez M, Pestell RG. The CCL5/CCR5 axis promotes metastasis in basal breast cancer. Oncoimmunology. 2013;2(4):e23660.
Man YG, Stojadinovic A, Mason J, et al. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J Cancer. 2013;4(1):84–95.
Wang X, Lang M, Zhao T, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. Oncogene. 2016; doi:10.1038/onc.2016.458.
Zhang Y, Lv D, Kim H-J, et al. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res. 2013;23(3):394–408.
Schlecker E, Stojanovic A, Eisen C, et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol. 2012;189(12):5602–11.
Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20(1):51–6.
Semenza GL. Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 2008;118(12):3835–7.
Balliet RM, Capparelli C, Guido C, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle. 2011;10(23):4065–73.
Hitosugi T, Kang S, Vander Heiden MG, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2010;2(97):1–16.
Zhang Y, Meng FY, Li WL, et al. Association of chemotactic factor receptor 5 gene with breast cancer. Genet Mol Res. 2013;12(4):5289–300.