Progression of prostate carcinoma is promoted by adipose stromal cell-secreted CXCL12 signaling in prostate epithelium

Abstract

Aggressiveness of carcinomas is linked with tumor recruitment of adipose stromal cells (ASC), which is increased in obesity. ASC promote cancer through molecular pathways not fully understood. Here, we demonstrate that epithelial–mesenchymal transition (EMT) in prostate tumors is promoted by obesity and suppressed upon pharmacological ASC depletion in HiMyc mice, a spontaneous genetic model of prostate cancer. CXCL12 expression in tumors was associated with ASC recruitment and localized to stromal cells expressing platelet-derived growth factor receptors Pdgfra and Pdgfrb. The role of this chemokine secreted by stromal cells in cancer progression was further investigated by using tissue-specific knockout models. ASC deletion of CXCL12 gene in the Pdgfr + lineages suppressed tumor growth and EMT, indicating stroma as the key source of CXCL12. Clinical sample analysis revealed that CXCL12 expression by peritumoral adipose stroma is increased in obesity, and that the correlating increase in Pdgfr/CXCL12 expression in the tumor is linked with decreased survival of patients with prostate carcinoma. Our study establishes ASC as the source of CXCL12 driving tumor aggressiveness and outlines an approach to treatment of carcinoma progression.

Partial Ablation of Non-Myogenic Progenitor Cells as a Therapeutic Approach to Duchenne Muscular Dystrophy

“…This has been demonstrated for tumors, in which ASCs become cancer-associated fibroblasts [36,42,43]. As with MSCs in other organs, ASCs are a key source of ECM and cytokines, which contribute to carcinoma progression [44]. We hypothesized that ASCs are recruited to muscle as it undergoes damage during DMD onset and contributes to FAPs.…”

“…In the other approach, fat tissue-derived FAP ablation was performed pharmacologically. For this, we used a hunter-killer peptide targeting ASCs, which was developed and validated by our group in a series of publications [38,44,55]. This bi-modal molecule, termed D-CAN, is based on a cyclic peptide WAT7 (sequence CSWKYWFGEC) binding to ∆DCN, a proteolytic isoform of Decorin [49], which is displayed on the surface of Pdgfrb+ ASC but not endothelial or smooth muscle cells [56].…”

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue

“…Pertinent to the endocrine nature of the AT, PPAT adipocytes and stromovascular cells secrete a myriad of adipokines capable of modulating PCa behavior, probably under the instruction of PCa cells [ 147 , 148 , 149 ]. Indeed, profound alterations in the PPAT epigenome, transcriptome, and secretome have been shown in lean and obese patients with benign prostatic hypertrophy (BPH), non-aggressive, and aggressive PCa [ 150 , 151 , 152 , 153 ].…”

“…Additionally, known as stromal-cell derived factor 1 (SDF-1), CXCL12 is another chemokine that is expressed by PPAT stroma and becomes increased in obesity, positively correlating with a decreased survival in patients with PCa [ 149 ]. Furthermore, CXCL12 expression is remarkably increased in the stromal vascular fraction of the PPAT and the stromal compartment of the ventral prostatic tissue of obese mice with myc-induced PCa [ 506 ].…”

Skeletal Muscle–Adipose Tissue–Tumor Axis: Molecular Mechanisms Linking Exercise Training in Prostate Cancer

“…The CXCL12/CXCR4 axis has been implicated in the recruitment of both local adjacent and distant ASCs, showing that distant adipose depots have a critical role in PCa [ 39 ]. In addition, the inactivation of CXCL12 in ASCs was shown to preclude tumor growth and the epithelial to mesenchymal transition in Myc-driven murine PCa models [ 40 ]. Importantly, ASCs can be recruited to the TME from adjacent or distant adipose depots via chemokine gradients [ 41 ].…”