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

Oncogene volume 41, pages 4633–4644 (2022)Cite this article

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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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Fig. 1: Immunofluorescence analysis of representative HMVP2 allograft tumor tissue sections from mice on control and DIO diets.
Fig. 2: CXCR4 antagonist (AMD3100) reduces HMVP2 allograft tumor growth and progression.
Fig. 3: CXCR4 knockout suppresses prostate cancer progression in obese HiMyc mice.
Fig. 4: Modulation of EMT, proliferation and stem cell markers by CXCR4 knock out in obese HiMyc mice.
Fig. 5: Combination of AMD3100 and D-CAN reduces HMVP2 allograft tumor growth.
Fig. 6: CXCR7 antagonist (CCX771) reduced HMVP2 PCa tumor growth.

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Acknowledgements

We would like to thank Steve Carbajal for his significant and extensive assistance to various aspects of this study. This study was supported by NIH grant R01 CA196259 (to JD and MGK).

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Authors and Affiliations

  1. Division of Pharmacology and Toxicology and Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, 78723, USA

    Songyeon Ahn, Achinto Saha, Rachel Clark & John DiGiovanni

  2. Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, 78723, USA

    Achinto Saha & John DiGiovanni

  3. Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723, USA

    Achinto Saha & John DiGiovanni

  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

    Mikhail G. Kolonin

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SA, AS, MK, RC, and JD conceived and designed the experiments. SA, AS, and RC performed the experiments. SA, AS, MK, and JD analyzed and interpreted the data and wrote the paper. JD provided administration and material support. All authors read and approved the final paper.

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Correspondence to John DiGiovanni.

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Ahn, S., Saha, A., Clark, R. et al. CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells. Oncogene 41, 4633–4644 (2022). https://doi.org/10.1038/s41388-022-02466-9

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