Abstract
Prostate cancer stem-like cells (PCSLC) are believed to be responsible for prostate cancer onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In prostate cancer patients, IL30/IL27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here, we asked whether IL30 may favor prostate cancer progression by conditioning PCSLCs and assessed the value of blocking IL30 to suppress tumor growth. IL30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion, and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization, and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL30 knockdown or knockout in PCSLCs. Collectively, these results mark IL30 as a key driver of PCSLC behavior. Targeting IL30 signaling may be a potential therapeutic strategy against prostate cancer progression and recurrence.Significance: IL30 plays an important role in regulating prostate cancer stem-like cell behavior and metastatic potential, therefore targeting this cytokine could hamper prostate cancer progression or recurrence. Cancer Res; 78(10); 2654-68. ©2018 AACR.
Highlights
Prostate cancer is the most common male malignancy and the second leading cause of male cancer-related deaths in Europe and the United States [1]
We have recently reported that endogenous IL30, originally identified as IL27p28 subunit, a novel polypeptide related to IL12p35 [11], is expressed in prostate cancer by both cancer cells and cancer- or lymph node (LN)–infiltrating leukocytes and that it displays tumor-promoting functions
We found that IL30 is produced in breast and prostate cancers, by both cancer cells and tumor- or LN-infiltrating leukocytes, mostly myeloid cells, in high-grade and stage of the diseases [13, 16]
Summary
Prostate cancer is the most common male malignancy and the second leading cause of male cancer-related deaths in Europe and the United States [1]. Mortality for prostate cancer is related to metastatic disease, which may develop in patients who become resistant to medical prostate cancer treatments, but it may manifest many years after a radical, and apparently successful, surgical cure of a localized prostate cancer. The immortal and pluripotent cancer-initiating cells, referred to as prostate cancer stem-like cells (PCSLC), which possess self-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). C. Sorrentino and S.L. Ciummo contributed to this article
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