PDGF receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAFs). Elevated expression of PDGF receptors on stromal CAFs are associated with metastasis and poor prognosis, but mechanism(s) that underlie this these connections are not understood. Here report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of co-cultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.
"A considerable number of studies demonstrate that STC1 promotes tumor migration and invasion , , , , with the exception of two studies in breast and ovarian cancer , . These inconsistent results may be due to the dynamic and complicated regulatory functions of STC1 in cell growth and apoptosis . "
[Show abstract][Hide abstract] ABSTRACT: Stanniocalcin-1 (STC1) and stanniocalcin-2 (STC2) are secreted glycoprotein hormones involved in various types of human malignancies. The roles of STC1 and STC2 in laryngeal squamous cell carcinoma (LSCC) remain unknown. We investigated correlations between STC1 and STC2 expression and clinicopathological or prognostic factors in LSCC.
Pre-surgical peripheral blood samples were collected between 2012 and 2013 from 62 patients with LSCC. Quantitative RT-PCR analysis was performed to examine mRNA levels of STC1 and STC2. Immunohistochemistry was performed to retrospectively analyze 90 paraffin-embedded LSCC tissue samples, which were obtained from patients who received surgery between 2006 and 2009. These patients did not have histories of treatment or malignancies. Univariate analysis of patient survival was performed by the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards model.
The relative mRNA levels of STC1 and STC2 in peripheral blood were significantly greater in LSCC patients than those of healthy volunteers (both P<0.05). STC2 protein expression in tumor tissues was associated with invasion into the thyroid cartilage, T-Stage, lymphatic metastasis, clinical stage, and pathological differentiation (all P<0.05). In addition, STC2 protein expression was an independent prognostic factor for overall survival in patients with LSCC (P = 0.025). In contrast, STC1 expression only correlated with clinical stage (P = 0.026) and was not an independent or significant prognostic factor.
Circulating STC1 and STC2 mRNA are potentially useful blood markers for LSCC. Our results strongly suggest that the STC2 protein, but not STC1, may be a valuable biomarker for LSCC malignancies and a prognostic marker for poor outcome following surgery. Future studies should examine STC2 as a novel molecular target for the treatment of LSCC.
PLoS ONE 04/2014; 9(4):e95466. DOI:10.1371/journal.pone.0095466 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF)-activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts and cultured resting fibroblasts. The most differentially expressed genes were reduced to a gene expression signature of 113 genes. The biological significance and prognostic capacity of this signature were investigated using four independent clinical breast cancer data sets. Concomitant high expression of PDGFβ receptor and its cognate ligands is associated with a high PDGF signature score. This supports the notion that the signature detects tumors with PDGF-activated stroma. Subsequent analyses indicated significant associations between high PDGF signature score and clinical characteristics, including HER2 positivity, estrogen receptor negativity, high tumor grade, and large tumor size. A high PDGF signature score is associated with shorter survival in univariate analysis. Furthermore, the high PDGF signature score acts as a significant marker of poor prognosis in multivariate survival analyses, including classic prognostic markers, Ki-67 status, a proliferation gene signature, or other recently described stroma-derived gene expression signatures.
American Journal Of Pathology 04/2013; 182(6). DOI:10.1016/j.ajpath.2013.02.018 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Genetic aberrations that are associated with platelet-derived growth factor receptor (PDGFR) activity are frequently found in glioblastomas (10 - 15%), dermatofibrosarcoma protuberans (≤ 100%) and gastrointestinal stromal tumors (5%). Sequencing studies have also identified mutations at lower frequency in common cancer types. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.
This review summarizes the present understanding of PDGF signaling in solid tumors based on experimental studies and clinical findings. It also provides a discussion of selected ongoing efforts to develop novel cancer therapies involving PDGFR inhibition with tyrosine kinase inhibitors or PDGFR-targeting monoclonal antibodies.
An increased molecular understanding of response and resistance mechanisms will be essential for therapeutic advances in PDGFR-directed cancer therapy. Further developments rely on clinical studies where systematic analyses of target status in malignant cells and in cells of the tumor stroma are included. Studies with combination therapies will be facilitated by selective PDGFR inhibitors with reduced side effects. Finally, development of improved companion diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.
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