Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop

Abstract

Obesity has long been linked with prostate cancer progression, although the underlying mechanism is still largely unknown. Here, we report that adipocytes promote the enrichment of prostate cancer stem cells (CSCs) through a vicious cycle of autocrine amplification. In the presence of adipocytes, prostate cancer cells actively secrete the peptide hormone cholecystokinin (CCK), which not only stimulates prostate CSC self-renewal, but also induces cathepsin B (CTSB) production of the adipocytes. In return, CTSB facilitates further CCK secretion by the cancer cells. More importantly, inactivation of CCK receptor not only suppresses CTSB secretion by the adipocytes, but also synergizes the inhibitory effect of CTSB inhibitor on adipocyte-promoted prostate CSC self-renewal. In summary, we have uncovered a novel mechanism underlying the mutual interplay between adipocytes and prostate CSCs, which may help explaining the role of adipocytes in prostate cancer progression and provide opportunities for effective intervention.

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

“…We investigated the prognosis significance of the upregulated and druggable genes. Excluding those genes with no clinical relevance, and those which have already been associated with PCa, such as Ctsb, Gpx2, Idh1, and Nos2 [60][61][62][63][64][65][66], we selected the antioxidant enzyme Srxn1 that had a strong correlation with patient outcome and has no previous related functional studies in PCa.…”

Contribution of Adipose Tissue to Development of Cancer

“…Pre-neoplastic prostatic intraepithelial neoplasia (PIN) progresses to invasive adenocarcinoma , in which extension of prostatic carcinoma through the prostatic capsule (extraprostatic extension) and resulting interaction with the surrounding adipose is an indicator of malignant progression and advanced histopathological stage (378). The periprostatic adipose depot unambiguously contributes to prostate cancer malignancy (326, 386, 396). In fact, interaction with periprostatic adipose tissue has been suggested to be amore important determinant of cancer recurrence than an invasive phenotype (192).…”

“…Periprostatic adipose tissue harvested from patients undergoing radical prostatectomy secreted IL-6 at concentrations 375 times greater than that in patient-matched serum and correlated with histological grade (117). Additionally, Tang et al (386) recently showed that co-culture of prostate cancer cells increased production of the cysteine protease cathepsin B by adipocytes. Further probing revealed that adipocyte co-culture induced secretion of the peptide hormone cholecystokinin (CCK) by prostate cancer cells, resulting in establishment of an autocrine/paracrine amplification loop in which CCK, acting through the CCK receptor CCKBR, induced expression of cancer stem cell markers such as CD49f and Sca-1 in prostate cancer cells and further production of cathepsin B by adipocytes.…”

Adipose Stem Cells and Cancer: Concise Review

“…Several studies have shown that the periprostatic adipose depot contributes to prostate cancer (PCa) malignancy . This may be due to the recruitment of ASCs from periprostatic adipose tissue to the prostate by chemokines secreted by PCa cells .…”