High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer

Choe, Deokyeong; Lee, Eunsook; Beeghly–Fadiel, Alicia; Wilson, Andrew J.; Whalen, Margaret M.; Adunyah, Samuel E.; Son, Deok‐Soo

doi:10.3390/cancers13195033

Cited by 5 publications

(2 citation statements)

References 51 publications

(77 reference statements)

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“…In another in vivo study, it was observed that C57B6 mice fed with HED and CRD and treated daily with the anti-diabetic agent metformin displayed a significant reduction in tumor volume along with a reduction in circulating levels of IGF-1, IL-6, and leptin in both plasma and ascetic fluid, similar to the CRD mice [194]. Overall, in vivo investigations demonstrated the positive correlation between obesity and ovarian cancer [234,235], although some of those did not investigate circulating leptin levels.…”

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confidence: 84%

Leptin: A Heavyweight Player in Obesity-Related Cancers

et al. 2023

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Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity’s effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.

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confidence: 84%

Leptin: A Heavyweight Player in Obesity-Related Cancers

et al. 2023

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“…CXCR2 is a chemokine secreted by adipocytes and has been associated with increased tumor burden in vivo compared to knock out animals, which had higher levels of ovarian cancer cells in ascites. CXCR2 is associated with obesity, a known risk factor for HGSOC ( 173 ) ( Figure 4A ).…”

Section: Microenvironment At Metastatic Nichesmentioning

confidence: 99%

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Ritch

Telleria

2022

Front. Endocrinol.

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Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

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Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions

Garcia,

Morales,

Yang

et al. 2024

Sci Rep

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The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2 −/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2 −/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2 −/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-75532-9.

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High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer

Cited by 5 publications

References 51 publications

Leptin: A Heavyweight Player in Obesity-Related Cancers

Leptin: A Heavyweight Player in Obesity-Related Cancers

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions

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