Regulation of prostate cancer progression by the tumor microenvironment

doi:10.1016/j.canlet.2015.12.022

Cancer Letters

Volume 380, Issue 1, 28 September 2016, Pages 340-348

https://doi.org/10.1016/j.canlet.2015.12.022 Get rights and content

Highlights

•
Both innate and adaptive immune cells contribute to prostate cancer progression.
•
Non-immune and immune stroma regulate each other and their effect on tumor cells.
•
Stromal cells exert their influence via direct cell-to-cell contact, soluble factors and extracellular vesicles.

Abstract

Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer.

Section snippets

Tumor–stroma microenvironment in prostate cancer

Reciprocal tumor–stroma interactions have been observed and well-appreciated in many forms of solid cancers including prostate cancer. The changes that occur in the stroma adjacent to tumors, called a desmoplastic response or “reactive stroma,” leads to aberrant growth and morphologic transformation of the stromal and connective tissues surrounding a tumor. This desmoplastic response contributes to the transition of stromal fibroblasts to myofibroblasts with a concomitant increase in the

The relationship between inflammation and prostate cancer

Inflammation has long been linked to the development of prostate cancer and it has been long recognized that chronic inflammation is associated with both benign as well as malignant prostate tissue [32]. Histologic studies have found that 80–90% of prostate cancer specimens had signs of immune infiltrate and, further, that high-grade disease was associated with increased inflammation [33]. Chronic inflammation with its persistent, ongoing immune response is thought to contribute to development

Circulating tumor cells (CTC) reprogram the local microenvironment to permit prostate cancer metastasis

Metastasis is a highly inefficient process. With the accelerated growth rate of many tumors, it has been increasingly recognized that millions of tumor cells are constantly shed from the primary tumors into the bloodstream and lymphatics detectable as circulating tumor cells (CTC). Given the high number of CTCs and the frequency of clinically apparent metastatic disease the actual rate of cancer cell colonization at metastatic sites appears to be extremely low. In order for CTCs to become

Conclusions

Prostate cancer has long been associated with changes in the normal prostatic tissues consisting of a combination of inflammatory cells such as macrophages and T cells as well as a non-inflammatory cells composed largely of cancer-associated stromal fibroblasts. These inflammatory and non-inflammatory elements in the microenvironment work in concert to produce a stromal microenvironment that is conducive to prostatic epithelial growth and transformation leading to the development of cancer (

Conflict of interest

The authors declare that they have no competing interests.

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Mini-reviewRegulation of prostate cancer progression by the tumor microenvironment

Highlights

Abstract

Section snippets

Tumor–stroma microenvironment in prostate cancer

The relationship between inflammation and prostate cancer

Circulating tumor cells (CTC) reprogram the local microenvironment to permit prostate cancer metastasis

Conclusions

Conflict of interest

Clin. Genitourin. Cancer

Cell

J. Urol

Semin. Cancer Biol

Cancer Cell

Immunity

Cancer Cell

Immunity

Exp. Mol. Pathol

Pharmacol. Ther

Eur. Urol

J. Immunol. Methods

Am. J. Pathol

Urology

Mod. Pathol

Eur. J. Cancer

Cancer Cell

Cancer Cell

Am. J. Pathol

Cell

Cell

Int. J. Biochem. Cell Biol

Kidney Int

Cancer statistics, 2014

CA Cancer J. Clin

Inflammation in prostate carcinogenesis

Nat. Rev. Cancer

Inflammation and prostate cancer: friends or foe?

Inflamm. Res

Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer

Clin. Cancer Res

Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts

Cancer Res

Bone marrow derived mesenchymal stem cells incorporate into the prostate during regrowth

PLoS ONE

Global gene expression analysis of reactive stroma in prostate cancer

Clin. Cancer Res

Coevolution of prostate cancer and bone stroma in three-dimensional coculture: implications for cancer growth and metastasis

Cancer Res

Malignant transformation in a nontumorigenic human prostatic epithelial cell line

Cancer Res

Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel

In Vitro Cell. Dev. Biol. Anim

Can cancer cells transform normal host cells into malignant cells?

Br. J. Cancer

Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium

Cancer Res

Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15

Cancer Res

TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia

Science

Extracellular vesicles: biology and emerging therapeutic opportunities

Nat. Rev. Drug Discov

Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis

Oncogene

miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer

Clin. Cancer Res

miR-154* and miR-379 in the DLK1-DIO3 microRNA mega-cluster regulate epithelial to mesenchymal transition and bone metastasis of prostate cancer

Clin. Cancer Res

The reactive stroma microenvironment and prostate cancer progression

Endocr. Relat. Cancer

Evolution of androgen receptor targeted therapy for advanced prostate cancer

Nat. Rev. Clin. Oncol

Innate immune recognition of cancer

Annu. Rev. Immunol

Neoantigens in cancer immunotherapy

Sci

Development of thymic Foxp3(+) regulatory T cells: TGF-beta matters

Eur. J. Immunol

Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial

Cancer Epidemiol. Biomarkers Prev

Mini-review
Regulation of prostate cancer progression by the tumor microenvironment