Ovarian cancer selective metastasizes to the omentum contributing to the poor prognosis associated with ovarian cancer. However, the mechanism underlining this propensity and therapeutic approaches to counter this process has not been fully elucidated. Here, we show that MCP-1 produced by omental adipocytes binding to its cognate receptor CCR-2 on ovarian cancer cells facilitates migration and omental metastasis by activating the PI3K/AKT/mTOR pathway and its downstream effectors HIF-1α and VEGF-A in cell lines, xenografts, and transgenic murine models. MCP-1 antibody significantly decreased tumor burden and increased survival of mice in vivo. Interestingly, metformin decreased omental metastasis at least partially by inhibiting MCP-1 secretion from adipocytes independent of direct effects on cancer cells. Together this suggests a novel target of MCP-1/CCR-2 axis that could benefit ovarian cancer patients.
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Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68:284–96.
Castadot P, Magne N, Berghmans T, Drowart A, Baeyens L, Smets D, et al. [Ovarian metastasis and lung adenocarcinoma: a case report]. Cancer Radiother. 2005;9:183–6.
Lim MC, Kang S, Lee KS, Han SS, Park SJ, Seo SS, et al. The clinical significance of hepatic parenchymal metastasis in patients with primary epithelial ovarian cancer. Gynecol Oncol. 2009;112:28–34.
Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005;5:355–66.
Tarin D, Price JE, Kettlewell MG, Souter RG, Vass AC, Crossley B. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res. 1984;44:3584–92.
Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res. 2013;19:961–8.
Robinson E, Fisher N, Stamelos V, Redman C, Richardson A. New strategies for the treatment of ovarian cancer. Biochem Soc Trans. 2014;42:125–9.
Bae HS, Kim HJ, Hong JH, Lee JK, Lee NW, Song JY. Obesity and epithelial ovarian cancer survival: a systematic review and meta-analysis. J Ovarian Res. 2014;7:41.
Yang HS, Yoon C, Myung SK, Park SM. Effect of obesity on survival of women with epithelial ovarian cancer: a systematic review and meta-analysis of observational studies. Int J Gynecol Cancer. 2011;21:1525–32.
Hoy AJ, Balaban S, Saunders DN. Adipocyte-tumor cell metabolic crosstalk in breast cancer. Trends Mol Med. 2017;23:381–92.
Xu XJ, Gauthier MS, Hess DT, Apovian CM, Cacicedo JM, Gokce N, et al. Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res. 2012;53:792–801.
Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282:2131–5.
Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19:162–71.
Sica A, Saccani A, Bottazzi B, Bernasconi S, Allavena P, Gaetano B, et al. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J Immunol. 2000;164:733–8.
Milliken D, Scotton C, Raju S, Balkwill F, Wilson J. Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin Cancer Res. 2002;8:1108–14.
Kojima R, Taniguchi H, Tsuzuki A, Nakamura K, Sakakura Y, Ito M. Hypertonicity-induced expression of monocyte chemoattractant protein-1 through a novel cis-acting element and MAPK signaling pathways. J Immunol. 2010;184:5253–62.
Pequeux C, Raymond-Letron I, Blacher S, Boudou F, Adlanmerini M, Fouque MJ, et al. Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis. Cancer Res. 2012;72:3010–9.
Tabuso M, Homer-Vanniasinkam S, Adya R, Arasaradnam RP. Role of tissue microenvironment resident adipocytes in colon cancer. World J Gastroenterol. 2017;23:5829–35.
Vande Broek I, Asosingh K, Vanderkerken K, Straetmans N, Van Camp B, Van Riet I. Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. Br J Cancer. 2003;88:855–62.
Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S, et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 2012;72:2768–79.
Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012;287:36593–608.
He YY, Du MR, Guo PF, He XJ, Zhou WH, Zhu XY, et al. Regulation of C-C motif chemokine ligand 2 and its receptor in human decidual stromal cells by pregnancy-associated hormones in early gestation. Hum Reprod. 2007;22:2733–42.
Guru SK, Pathania AS, Kumar S, Ramesh D, Kumar M, Rana S, et al. Secalonic acid-D represses HIF1alpha/VEGF-mediated angiogenesis by regulating the Akt/mTOR/p70S6K signaling cascade. Cancer Res. 2015;75:2886–96.
Lu CH, Hung YJ, Hsieh PS. Additional effect of metformin and celecoxib against lipid dysregulation and adipose tissue inflammation in high-fat fed rats with insulin resistance and fatty liver. Eur J Pharmacol. 2016;789:60–67.
Al-Wahab Z, Mert I, Tebbe C, Chhina J, Hijaz M, Morris RT, et al. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction. Oncotarget. 2015;6:10908–23.
Rodriguez GM, Galpin KJC, McCloskey CW, Vanderhyden BC. The tumor microenvironment of epithelial ovarian cancer and its influence on response to immunotherapy. Cancers. 2018;10:8–17.
Wang YX, Zhu N, Zhang CJ, Wang YK, Wu HT, Li Q, et al., Friend or foe: multiple roles of adipose tissue in cancer formation and progression. J Cell Physiol. 2019;8–9.
Yu H, Dilbaz S, Cossmann J, Hoang AC, Diedrich V, Herwig A, et al. Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages. J Clin Investig. 2019;130:2485–99.
Shen H, He M, Lin R, Zhan M, Xu S, Huang X, et al. PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway. J Exp Clin Cancer Res. 2019;38:247.
Wojnarowicz P, Gambaro K, de Ladurantaye M, Quinn MC, Provencher D, Mes-Masson AM, et al. Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity. Oncogenesis. 2012;1:e27.
Yumimoto K, Sugiyama S, Mimori K, Nakayama KI. Potentials of C–C motif chemokine 2-C-C chemokine receptor type 2 blockers including propagermanium as anticancer agents. Cancer Sci. 2019;2090–1.
Mizutani K, Roca H, Varsos Z, Pienta KJ. Possible mechanism of CCL2-induced Akt activation in prostate cancer cells. Anticancer Res. 2009;29:3109–13.
Furukawa S, Soeda S, Kiko Y, Suzuki O, Hashimoto Y, Watanabe T, et al. MCP-1 promotes invasion and adhesion of human ovarian cancer cells. Anticancer Res. 2013;33:4785–90.
Sierra-Filardi E, Nieto C, Dominguez-Soto A, Barroso R, Sanchez-Mateos P, Puig-Kroger A, et al. CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. J Immunol. 2014;192:3858–67.
Manome Y, Wen PY, Hershowitz A, Tanaka T, Rollins BJ, Kufe DW, et al. Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors. Cancer Immunol Immunother. 1995;41:227–35.
Liu GX, Zhang X, Li S, Koiiche RD, Sindsceii JH, Song H. Monocyte chemotactic protein-1 and CC chemokine receptor 2 polymorphisms and prognosis of renal cell carcinoma. Tumour Biol. 2013;34:2741–6.
Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C–C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010;102:522–8.
Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res. 2012;5:536–43.
Sikka A, Kaur M, Agarwal C, Deep G, Agarwal R. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle. 2012;11:1374–82.
Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13:483–91.
Romero IL, Mukherjee A, Kenny HA, Litchfield LM, Lengyel E. Molecular pathways: trafficking of metabolic resources in the tumor microenvironment. Clin Cancer Res. 2015;21:680–6.
Giuliani M, Gui B, Valentini AL, di Giovanni SE, Micco M, Rodolfino E, et al. Early detection of recurrence or progression disease in patients with ovarian cancer after primary debulking surgery: a diagnostic challenge still unresolved. Correlation between CT findings and CA 125 levels. Minerva Ginecol. 2017;8.
Pienta KJ, Machiels JP, Schrijvers D, Alekseev B, Shkolnik M, Crabb SJ, et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Investig New Drugs. 2013;31:760–8.
Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut. 2017;66:157–67.
Baldan V, Griffiths R, Hawkins RE, Gilham DE. Efficient and reproducible generation of tumour-infiltrating lymphocytes for renal cell carcinoma. Br J Cancer. 2015;112:1510–8.
Wang Y, Chen JN, Yang L, Li J, Wu W, Huang M, et al. Tumor-contacted neutrophils promote metastasis by a CD90-TIMP-1 juxtacrine-paracrine Loop. Clin Cancer Res. 2018. (Line 8–30 in a manuscript version)
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503.
Xu TP, Huang MD, Xia R, Liu XX, Sun M, Yin L, et al. Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression. J Hematol Oncol. 2014;7:63.
N. Cancer Genome Atlas Research. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
Teng PN, Wang G, Hood BL, Conrads KA, Hamilton CA, Maxwell GL, et al. Identification of candidate circulating cisplatin-resistant biomarkers from epithelial ovarian carcinoma cell secretomes. Br J Cancer. 2014;110:123–32.
We thank our patients for donating biospecimens and clinical data. We thank Dr X. Jin and Dr Z. Yang for donating the SKOV3-ERFP and SKOV3 G3 cell lines. We thank Prof. Benjamin K. Tsang for donating the C13 and OV2008 cell lines.
This study was supported by the National Key R&D Program of China (2016YFC1303100), the National Basic Research Program of China (973 Program, 2015CB553903), Nature and Science Foundation of China (81272859, 81572569, 81402163, 81402164, 81501530, 81671394, and 81370469), the International S&T Cooperation Program of China (No. 2013DFA31400). GBM has support from NIH P50CA217685, Ovarian Cancer Research Foundation, and a kind gift from the Adelson Medical Research Fund.
Conflict of interest
GBM is a SAB member or Consultant with AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda, has Stock Options or Financial arrangements with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, Tarveda, has Licensed Technology with a HRD assay to Myriad Genetics and a DSP patent with Nanostring and has sponsored Research with Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Immunomet, Ionis, Komen Research Foundation, Nanostring, Ovarian Cancer Research Foundation, Pfizer, Prospect Creek Foundation, and Takeda/Millennium Pharmaceuticals. The authors declare that they have no conflict of interest.
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Sun, C., Li, X., Guo, E. et al. MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene (2019) doi:10.1038/s41388-019-1090-1