Epithelial–mesenchymal transition (EMT) is a complex molecular program that regulates changes in cell morphology and function during embryogenesis and tissue development. EMT also contributes to tumor progression and metastasis. Cells undergoing EMT expand out of and degrade the surrounding microenvironment to subsequently migrate from the primary site. The mesenchymal phenotype observed in fibroblasts is specifically important based on the expression of smooth muscle actin (α-SMA), fibroblast growth factor (FGF), fibroblast-specific protein-1 (FSP1), and collagen to enhance EMT. Although EMT is not completely dependent on EMT regulators such as Snail, Twist, and Zeb-1/-2, analysis of upstream signaling (i.e., TGF-β, EGF, Wnt) is necessary to understand tumor EMT more comprehensively. Tumor epithelial–fibroblast interactions that regulate tumor progression have been identified during prostate cancer. The cellular crosstalk is significant because these events influence therapy response and patient outcome. This review addresses how canonical EMT signals originating from prostate cancer fibroblasts contribute to tumor metastasis and recurrence after therapy.

Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.

The major cellular components of tumor microenvironment, referred to as the cancer stroma, are composed of cancer-associated fibroblasts that support tumor epithelial growth, invasion and therapeutic resistance. Thus when we speak of developing therapies that address tumor heterogeneity it is not only a matter of different mutations within the tumor epithelia. While individual mutations in the stromal compartment are controversial, the heterogeneity in fibroblastic population in a single tumor is not up for debate. Cooperative interaction among heterotypic fibroblasts and tumor cells contribute to cancer progression. Therefore to tackle solid tumors, we need to understand its complex microenvironment. Here we review some seminal developments in the field of tumor microenvironment, mainly focusing on cancer-associated fibroblast.

Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

Prostate cancer develops through a stochastic mechanism whereby precancerous lesions on occasion progress to multifocal adenocarcinoma. Analysis of human benign and cancer prostate tissues revealed heterogeneous loss of TGF-β signaling in the cancer-associated stromal fibroblastic cell compartment. To test the hypothesis that prostate cancer progression is dependent on the heterogeneous TGF-β responsive microenvironment, a tissue recombination experiment was designed in which the ratio of TGF-β responsive and nonresponsive stromal cells was varied. Although 100% TGF-β responsive stromal cells supported benign prostate growth and 100% TGF-β nonresponsive stromal cells resulted in precancerous lesions, only the mixture of TGF-β responsive and nonresponsive stromal cells resulted in adenocarcinoma. A computational model was used to resolve a mechanism of tumorigenic progression in which proliferation and invasion occur in two independent steps mediated by distinct stromally derived paracrine signals produced by TGF-β nonresponsive and responsive stromal cells. Complex spatial relationships of stromal and epithelial cells were incorporated into the model on the basis of experimental data. Informed by incorporation of experimentally derived spatial parameters for complex stromal–epithelial relationships, the computational model indicated ranges for the relative production of paracrine factors by each cell type and provided bounds for the diffusive range of the molecules. Because SDF-1 satisfied model predictions for an invasion-promoting paracrine factor, a more focused computational model was subsequently used to investigate whether SDF-1 was the invasion signal. Simulations replicating SDF-1 expression data revealed the requirement for cooperative SDF-1 expression, a prediction supported biologically by heterotypic stromal interleukin-1β signaling between fibroblastic cell populations. The cancer stromal field effect supports a functional role for the unaltered fibroblasts as a cooperative mediator of cancer progression. Cancer Res; 71(10); 3459–70. ©2011 AACR.