Fibroblast and prostate tumor cell cross-talk: Fibroblast differentiation, TGF-β, and extracellular matrix down-regulation
ABSTRACT Growth and survival of tumors at a site of metastasis involve interactions with stromal cells in the surrounding environment. Stromal cells aid tumor cell growth by producing cytokines as well as by modifying the environment surrounding the tumor through modulation of the extracellular matrix (ECM). Small leucine-rich proteoglycans (SLRPs) are biologically active components of the ECM which can be altered in the stroma surrounding tumors. The influence tumor cells have on stromal cells has been well elucidated. However, little is understood about the effect metastatic cancer cells have on the cell biology and behavior of the local stromal cells. Our data reveal a significant down-regulation in the expression of ECM components such as collagens I, II, III, and IV, and the SLRPs, decorin, biglycan, lumican, and fibromodulin in stromal cells when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145. Interestingly, TGF-β down-regulation was observed in stromal cells, as well as actin depolymerization and increased vimentin and α5β1 integrin expression. MT1-MMP expression was upregulated and localized in stromal cell protrusions which extended into the ECM. Moreover, enhanced stromal cell migration was observed after cross-talk with metastatic prostate tumor cells. Xenografting metastatic prostate cancer cells together with "activated" stromal cells led to increased tumorigenicity of the prostate cancer cells. Our findings suggest that metastatic prostate cancer cells create a metastatic niche by altering the phenotype of local stromal cells, leading to changes in the ECM.
- SourceAvailable from: Ying Dong
[Show abstract] [Hide abstract]
- "Of note, as reported above for other KLKs, we also identified the TGF-␤1 signaling axis as a key KLK4 target (our unpublished data). TGF-␤1 is one of the key growth factors implicated in transforming normal fibroblasts into cancer-associated myofibroblasts , a process integral to cancer progression as the latter phenotype is both permissive and supportive of cancerous outgrowth . Thus, KLK4 and indeed other KLKs that are yet to be screened for fibroblast interactions using similar approaches, may contribute toward cancer progression via modulation of the stromal microenvironment. "
ABSTRACT: Rapidly developing proteomic tools are improving detection of deregulated kallikrein-related peptidase (KLK) expression, at the protein level, in prostate and ovarian cancer, as well as facilitating the determination of functional consequences downstream. Mass spectrometry (MS)-driven proteomics uniquely allows for the detection, identification and quantification of thousands of proteins in a complex protein pool, and this has served to identify certain KLKs as biomarkers for these diseases. In this review we describe applications of this technology in KLK biomarker discovery, and elucidate MS-based techniques which have been used for unbiased, global screening of KLK substrates within complex protein pools. Although MS-based KLK degradomic studies are limited to date, they helped to discover an array of novel KLK substrates. Substrates identified by MS-based degradomics are reported with improved confidence over those determined by incubating a purified or recombinant substrate and protease of interest, in vitro. We propose that these novel proteomic approaches represent the way forward for KLK research, in order to correlate proteolysis of biological substrates with tissue-related consequences, toward clinical targeting of KLK expression and function for cancer diagnosis, prognosis and therapies. This article is protected by copyright. All rights reserved.PROTEOMICS - CLINICAL APPLICATIONS 06/2014; 8(5-6). DOI:10.1002/prca.201300098 · 2.96 Impact Factor
[Show abstract] [Hide abstract]
- "Mouse model experiments have shown that disruption of decorin expression can increase intestinal tumor formation 19 and accelerate lymphoma formation 20. In vitro findings have shown that decorin expression by fibroblasts is reduced when they are grown together with prostate cancer cell lines 21. Due to its tumor suppressive potency, decorin was called a “guardian from the matrix” in a recent review 22. "
ABSTRACT: Decorin is a small leucine-rich proteoglycan, synthesized and deposited by fibroblasts in the stroma where it binds to collagen I. It sequesters several growth factors and antagonizes numerous members of the receptor tyrosine kinase family. In experimental murine systems, it acted as a potent tumor suppressor. Examining the Human Protein Atlas online database of immunostained tissue samples we have surveyed decorin expression in silico in several different tumor types, comparing them with corresponding normal tissues. We found that decorin is abundantly secreted and deposited in normal connective tissue but its expression is consistently decreased in the tumor microenvironment. We developed a software to quantitate the difference in expression. The presence of two closely related proteoglycans in the newly formed tumor stroma indicated that the decreased decorin expression was not caused by the delay in proteoglycan deposition in the newly formed connective tissue surrounding the tumor.Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.231 · 2.50 Impact Factor
[Show abstract] [Hide abstract]
- "Several other studies show inhibition of production of extracellular matrix (ECM) components by CAFs. For example, an expression of collagens I, II, III, IV, fibromodulin, and proteoglycans (decorin, biglycan, lumican) in stromal cells, when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145, is significantly down-regulated (35). Down-regulation of procollagens I, III, IV, fibronectin, and CS proteoglycans (5–10-fold) are detected in tumorigenic NbF-1 cells versus non-tumorigenic NbF-1 cultures (36). "
ABSTRACT: Heparan sulfates (HSs) are key components of mammalian cells surface and extracellular matrix. Structure and composition of HS, generated by HS-biosynthetic system through non-template-driven process, are significantly altered in cancer tissues. The aim of this study was to investigate the involvement of HS-metabolic machinery in prostate carcinogenesis. Transcriptional patterns of HS-metabolic enzymes (EXT1, EXT2, NDST1, NDST2, GLCE, 3OST1/HS3ST1, SULF1, SULF2, HPSE) were determined in normal, benign, and cancer human prostate tissues and cell lines (PNT2, LNCaP, PC3, DU145). Stability of the HS-metabolic system patterns under the pressure of external or internal stimuli was studied. Overall impairment of transcriptional activity of HS-metabolic machinery was detected in benign prostate hyperplasia, while both significant decrease in the transcriptional activity and changes in the expression patterns of HS metabolism-involved genes were observed in prostate tumors. Prostate cancer cell lines possessed specific transcriptional patterns of HS metabolism-involved genes; however, expression activity of the system was similar to that of normal prostate PNT2 cells. HS-metabolic system was able to dynamically react to different external or internal stimuli in a cell type-dependent manner. LNCaP cells were sensitive to the external stimuli (5-aza-deoxycytidin or Trichostatin A treatments; co-cultivation with human fibroblasts), whereas PC3 cells almost did not respond to the treatments. Ectopic GLCE over-expression resulted in transcriptional activation of HS-biosynthetic machinery in both cell lines, suggesting an existence of a self-regulating mechanism for the coordinated transcription of HS metabolism-involved genes. Taken together, these findings demonstrate impairment of HS-metabolic system in prostate tumors in vivo but not in prostate cancer cells in vitro, and suggest that as a potential microenvironmental biomarker for prostate cancer diagnostics and treatment.Frontiers in Oncology 04/2014; 4:79. DOI:10.3389/fonc.2014.00079