Abstract
Simple SummaryObesity contributes to one-fifth of cancer deaths. Ovarian cancer (OC) progression is frequently asymptomatic, making its early detection difficult and its chance of survival low. OC expresses highly tumorigenic chemokines, CXCL1/8, of which the specific receptor CXCR2 is increased in the adipocytes. So, the CXCL1/8-CXCR2 axis may appear as a molecular link between obesity and OC. Here, we generated adipocyte-specific CXCR2 conditional knockout (cKO) mice to investigate how this CXCR2 cKO affects the peritoneal dissemination of OC under obese conditions. High-fat, diet-induced obese mice had a shorter survival than lean mice. Particularly, obese cKO mice had a reduced tumor burden but increased ascites accumulation, showing a decreased floating tumor burden in ascites, as well as proliferation and macrophage infiltration in tumors compared to obese wild-type mice. Despite the ascites accumulation, adipocyte-specific CXCR2 cKO reduced the obesity-induced tumor burden, likely altering the peritoneal tumor microenvironment of OC.Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC.
Highlights
Obesity, a disease defined by excessive fat accumulation which impairs health, is an escalating global epidemic: according to the World Health Organization, there are predicted to be 1.12 billion obese adults by 2030 [1]
All mice were ovariectomized to avoid the suppressive effects of estrogen on obesity [28,29] and to create a pseudo-postmenopausal state, as most ovarian cancers develop after menopause
The adipose tissues in high-fat diet (HFD)-fed WT mice showed a larger increase in CXC chemokine receptor type 2 (CXCR2) protein levels compared to normal diet (ND)-fed mice (Figure 1B), indicating an obesity-induced CXCR2 expression
Summary
A disease defined by excessive fat accumulation which impairs health, is an escalating global epidemic: according to the World Health Organization, there are predicted to be 1.12 billion obese adults by 2030 [1]. Chemokines are recognized as critical mediators in the tumor microenvironment and play a central role in regulating the inflammatory response, contributing to the progression and metastasis of OC [12] Chemokines, such as CCL20, CXCL1–3, CXCL5, and CXCL8, are highly expressed in OC cells and the tumor microenvironment of OC [13,14,15]. CXCR2 knockout (KO) mice had a significantly reduced tumor burden in other cancers, such as murine lung, prostate, and renal cancer models, compared to CXCR2 wild-type (WT) mice [22,23,24] These findings indicate that CXCR2 may be a critical molecular target to attenuate the progression of OC. These CXCR2 cKO mice were employed to clarify the roles of adipocyte-derived CXCR2 signaling in the peritoneal dissemination of OC
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