2. Academic Validation
  3. CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells

CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells

  • Oncogene. 2022 Oct;41(41):4633-4644. doi: 10.1038/s41388-022-02466-9.
Songyeon Ahn 1,  Achinto Saha 1 2 3,  Rachel Clark 1,  Mikhail G Kolonin 4,  John DiGiovanni 5 6 7
Affiliations

Affiliations

  • 1 Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, 78723, USA.
  • 2 Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, 78723, USA.
  • 3 Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723, USA.
  • 4 The Brown Foundation Institute of Molecular Medicine for the Prevention of Disease, The University of Texas Health Sciences Center at Houston, Houston, TX, 77030, USA.
  • 5 Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, 78723, USA. [email protected].
  • 6 Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, 78723, USA. [email protected].
  • 7 Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723, USA. [email protected].
PMID: 36088505 DOI: 10.1038/s41388-022-02466-9
Abstract

Obesity is associated with increased prostate Cancer (PCa) progression and higher mortality, however, the mechanism(s) remain still unclear. Here, we investigated signaling by the ASC-secreted chemokine CXCL12 in a mouse allograft model of PCa and in HiMyc mice in the context of diet-induced obesity. Treatment of mice with CXCR4 Antagonist inhibited CXCL12-induced signaling pathways, tumor growth and EMT in HMVP2 allograft tumors. Similar results were obtained following prostate epithelium-specific deletion of CXCR4 in HiMyc mice. We also show that CXCR4 signaling regulates expression of JMJD2A Histone Demethylase and histone methylation which is modulated by AMD3100. Importantly, treatment with a CXCR7 Antagonist also inhibited allograft tumor growth and EMT. The current results demonstrate that both CXCR4 and CXCR7 play an important role in Cancer progression and establish CXCL12 signaling pathways, activated in obesity, as potential targets for PCa intervention. In addition, other factors secreted by ASCs, may also contribute to Cancer aggressiveness in obesity.

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