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Epithelial-mesenchymal transition and inflammation at the site of the primary tumor.

ABSTRACT: Tumor growth and progression are the products of complex signaling networks between different cell types within the tumor and its surrounding stroma. In particular, established tumors are known to stimulate an inflammatory reaction via the secretion of cytokines, chemokines, and growth factors that favor the recruitment of a range of infiltrating immune cell populations into the tumor microenvironment. While potentially able to exert tumor control, this inflammatory reaction is typically seized upon by the tumor to promote its own growth and progression towards metastasis. This review focuses on recent advances in understanding how an established tumor can initiate an inflammatory response via the release of pro-inflammatory mediators, such as IL-6 and IL-8, and their roles in cancer metastasis. In particular, the role of the epithelial-mesenchymal transition (EMT), a phenotypic switch observed in carcinomas that promotes progression towards metastasis, is discussed here in relation to cancer inflammation.

SUBMITTER: Dominguez C

PROVIDER: S-EPMC5698091 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Epithelial-mesenchymal transition and inflammation at the site of the primary tumor.

Dominguez Charli C David Justin M JM Palena Claudia C

Seminars in cancer biology 20170818

Tumor growth and progression are the products of complex signaling networks between different cell types within the tumor and its surrounding stroma. In particular, established tumors are known to stimulate an inflammatory reaction via the secretion of cytokines, chemokines, and growth factors that favor the recruitment of a range of infiltrating immune cell populations into the tumor microenvironment. While potentially able to exert tumor control, this inflammatory reaction is typically seized ...[more]

PMID: 28823497

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Project description:Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.

Project description:IntroductionThe presence of circulating tumor cells (CTC) in breast cancer might be associated with stem cell-like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, to be able to disseminate and metastasize, CTC must be able to perform epithelial-mesenchymal transition (EMT). We studied the expression of three EMT markers and the stem cell marker ALDH1 in CTC from 502 primary breast cancer patients. Data were correlated with the presence of disseminated tumor cells (DTC) in the bone marrow (BM) and with clinicopathological data of the patients.MethodsA total of 2 × 5 ml of blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1, HER2 and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [TWIST1, Akt2, phosphoinositide kinase-3 (PI3Kα)] and separately for the tumor stem cell marker ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Two BM aspirates from all patients were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3.ResultsNinety-seven percent of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts, respectively. CTC were detected in 97/502 (19%) patients. At least one of the EMT markers was expressed in 29% and ALDH1 was present in 14% of the samples, respectively. Interestingly, 5% of the ALDH1-positive and 18% of the EMT-positive patients were CTC-negative based on the cut-off level determined for CTC-positivity applying the AdnaTest BreastCancer. DTC in the BM were detected in 107/502 (21%) patients and no correlation was found between BM status and CTC positivity (P = 0.41). The presence of CTC, EMT and ALDH1 expression was not correlated to any of the prognostic clinical markers.ConclusionsOur data indicate that (1) a subset of primary breast cancer patients shows EMT and stem cell characteristics and (2) the currently used detection methods for CTC are not efficient to identify a subtype of CTC which underwent EMT. (3) The clinical relevance on prognosis and therapy response has to be further evaluated in a prospective trial.

Dataset Information

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor.

Publications

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor.

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