Cross-talk between Paracrine-Acting Cytokine and Chemokine Pathways Promotes Malignancy in Benign Human Prostatic Epithelium

Ao, Mingfang; Franco, Omar E.; Park, Dean; Raman, Dayanidhi; Williams, Karin; Hayward, Simon W.

doi:10.1158/0008-5472.can-06-3946

Cited by 257 publications

(242 citation statements)

References 44 publications

(69 reference statements)

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“…While other investigators have studied the direct oncogenic activation of epithelial cells, we chose to apply two different stromal-based assays to indirectly test the effects on subpopulations of prostatic epithelia. First, CAFs derived from primary prostate cancer specimens show distinct genotypic and phenotypic differences compared to their nonmalignant matched controls and have been studied extensively in this BPH-1 cell assay [13,14,36,37]. The second model of hormonal carcinogenesis is based on administration of high doses of testosterone in combination with 17b-estradiol.…”

Section: Discussionmentioning

confidence: 99%

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

et al. 2012

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Normal prostatic epithelium is composed of basal and luminal cells. Prostate cancer can be initiated in both benign basal and luminal stem cells, but because basal cell markers are not expressed in patient tumors, the former result was unexpected. Since the cells of origin of prostate cancer are important therapeutic targets, we sought to provide further proof that basal stem cells have tumorigenic potential. Prostatic basal cells were enriched based on a2b1integrin hi expression and further enriched for stem cells using CD133 in nontumorigenic BPH-1 cells. Human embryonic stem cells (hESCs) were also used as a source of normal stem cells. To test their tumorigenicity, we used two alternate stromal-based approaches; (a) recombination with human cancer-associated fibroblasts (CAFs) or (b) recombination with embryonic stroma (urogenital mesenchyme) and treated host mice with testosterone and 17b-estradiol. Enriched a2b1integrin hi basal cells from BPH-1 cells resulted in malignant tumor formation using both assays of tumorigenicity. Surprisingly, the tumorigenic potential did not reside in the CD133 1 stem cells but was consistently observed in the CD133 2 population. CAFs also failed to induce prostatic tumors from hESCs. These data confirmed that benign human basal cells include cells of origin of prostate cancer and reinforced their importance as therapeutic targets. In addition, our data suggested that the more proliferative CD133 2 basal cells are more susceptible to tumorigenesis compared to the CD133 1 -enriched stem cells. These findings challenge the current dogma that normal stem cells and cells of origin of cancer are the same cell type(s).

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Section: Discussionmentioning

confidence: 99%

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

et al. 2012

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“…Likewise, DU145 treated with miR-15/16 fibroblast CM (miR-15/16 viruses were used at a final concentration of 5 Â 10 5 TU/ml) showed the same decrease in signaling activation (Supplementary Figure 2f). miR-15 and miR-16 block stromal tumor support in vivo Microenvironment aberrant stimuli can transform nonneoplastic prostate epithelium cells into cancer cells (Hayward et al, 2001;Ao et al, 2007). Moreover, the cancer-stroma interaction can enhance survival and tumor spreading, leading to metastasis formation (Thiery, 2002;Kalluri and Weinberg, 2009;Polyak and Weinberg, 2009).…”

Section: Fgf-2 and Fgfr1 Are New Targets Of Mir-15 And Mir-16mentioning

confidence: 99%

“…In this context, the stroma acquires tumor-enhancing properties and is defined as 'reactive' (Tuxhorn et al, 2002;Josson et al, 2010). It has been suggested that a dysfunctional microenvironment can turn a prostatic hypertrophy into a prostate tumor through a process that involves vessel neo-formation and acquisition of androgen insensitivity (Chung et al, 1989;Wu et al, 1994;Hayward et al, 2001;Ao et al, 2007). Among the cell types cohabitating a reactive stroma, carcinomaassociated fibroblasts (CAFs) are thought to be the main actors, even though it is still unclear if these cells undergo irreversible alterations or epigenetic changes during tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

et al. 2011

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The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.

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“…While epithelial in origin, the tumor microenvironment plays a critical role in prostate adenocarcinoma pathogenesis, for example, stromal signaling is required for tumor initiation, tumor cell proliferation, angiogenesis, metastasis and diminishes therapy response 2, 3, 4. These protumorigenic actions of the tumor microenvironment are largely mediated via the secretion of paracrine‐acting factors, including chemokines, cytokines, growth factors, extracellular matrix (ECM) components and ECM remodeling enzymes 5.…”

mentioning

confidence: 99%

“…While CAFs may originate from multiple sources (e.g., pericytes, endothelial cells and bone marrow‐derived circulating precursors), growing evidence indicates that the tumor‐associated stroma predominantly derives from precursors in the local tumor microenvironment 10. In particular, local resident fibroblasts are thought to be activated via tumor cell‐derived soluble factors of which transforming growth factor beta 1 (TGFβ1) is the most characterized and activates prostatic fibroblasts to a CAF‐like phenotype in vitro and in vivo 2, 8. Notably, circulating TGFβ1 levels positively correlate with PCa risk, rapid disease progression and poor outcome 11, 12…”

mentioning

confidence: 99%

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Sampson

Brunner

Weber

et al. 2018

Intl Journal of Cancer

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Carcinoma‐associated fibroblasts (CAFs) play a key onco‐supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)‐producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1‐mediated activation of primary prostate human fibroblasts to a CAF‐like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine‐mediated PCa‐relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri‐tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF‐associated marker expression and migration of TGFβ1‐activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA‐mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1‐driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1‐activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4‐ and TGFβ receptor‐dependent manner. Importantly, GKT137831 also attenuated PCa cell‐driven fibroblast activation. Collectively, these findings suggest the TGFβ‐Nox4 signaling axis is a key interface to dysregulated reciprocal stromal–epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal‐targeted approach to complement current PCa treatment modalities.

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Cross-talk between Paracrine-Acting Cytokine and Chemokine Pathways Promotes Malignancy in Benign Human Prostatic Epithelium

Abstract: The present study explores the mechanisms by which human prostatic carcinoma-associated fibroblasts

Cited by 257 publications

References 44 publications

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

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