A Novel Bone Morphogenetic Protein Signaling in Heterotypic Cell Interactions in Prostate Cancer

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Cancer Research (Impact Factor: 9.33). 02/2008; 68(1):198-205. DOI: 10.1158/0008-5472.CAN-07-5074
Source: PubMed


We examined the effect of the extracellular bone morphogenetic protein (BMP) 2 and 7, which are up-regulated in the prostate adenocarcinomas of the conditional Pten deletion mouse model, on primary cultures of cancer-associated fibroblasts (CAF) derived from these tumors. In the CAF, we show that BMP2 or BMP7, but not transforming growth factor beta-1, can strikingly stimulate secretion of stromal cell-derived factor-1 (SDF-1), also known as CXCL12. The CAF cells express type I and type II BMP receptors as well as the receptor for SDF-1, CXCR4. SDF-1 activation is associated with BMP-induced Smad phosphorylation, and the stimulatory effect is blocked by BMP antagonist, noggin. The findings that BMP treatment can increase SDF-1 pre-mRNA levels in a time-dependent manner and actinomycin D treatment can abolish stimulatory effect of BMP suggest a transcriptional modulation of SDF-1 by BMP signaling. Using a human microvascular endothelial cell line, we show that SDF-1 present in the conditioned medium from the stimulated CAF can significantly induce tube formation, an effect relating to angiogenic function. Furthermore, we found that BMP2 can also protect the CAF from serum starvation-induced apoptosis independent of SDF-1, implying that BMP may induce other factors to sustain the survival of these cells. In short, this report establishes a novel BMP-SDF-1 axis in the prostate tumor along with a new prosurvival effect of BMP that when considered together with our previously described oncogenic properties of BMP indicate a circuitry for heterotypic cell interactions potentially critical in prostate cancer.

9 Reads
  • Source
    • "We were interested in determining whether this increase may have distinct effects on cells in the tumor stromal microenvironment, which can have paracrine effects on carcinoma cells. Recently, it was discovered that fibroblasts derived from mouse prostate tumors stimulated by BMPs can increase angiogenesis via the upregulation of the chemokine SDF1α/CXCL12 [12]. This finding was supported by earlier work demonstrating that BMPs were playing active roles in the promotion of prostate tumorigenesis and subsequently bone metastases [18], [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone Morphogenetic Proteins (BMPs) are secreted cytokines that are part of the Transforming Growth Factor β (TGFβ) superfamily. BMPs have been shown to be highly expressed in human breast cancers, and loss of BMP signaling in mammary carcinomas has been shown to accelerate metastases. Interestingly, other work has indicated that stimulation of dermal fibroblasts with BMP can enhance secretion of pro-tumorigenic factors. Furthermore, treatment of carcinoma-associated fibroblasts (CAFs) derived from a mouse prostate carcinoma with BMP4 was shown to stimulate angiogenesis. We sought to determine the effect of BMP treatment on mammary fibroblasts. A large number of secreted pro-inflammatory cytokines and matrix-metallo proteases (MMPs) were found to be upregulated in response to BMP4 treatment. Fibroblasts that were stimulated with BMP4 were found to enhance mammary carcinoma cell invasion, and these effects were inhibited by a BMP receptor kinase antagonist. Treatment with BMP in turn elevated pro-tumorigenic secreted factors such as IL-6 and MMP-3. These experiments demonstrate that BMP may stimulate tumor progression within the tumor microenvironment.
    PLoS ONE 06/2013; 8(6):e67533. DOI:10.1371/journal.pone.0067533 · 3.23 Impact Factor
  • Source
    • "However, cancer cells co-cultured with normal HPMCs also have reduced E-cadherin expression (Fig. 2). According to recent reports, CAFs are implicated in cancer by producing high quantities of stromal-derived factor-1α (SDF-1α), also known as chemokine CXCL12 (31); SDF-1α expression is higher in mesothelial cells than in other organs (32). Although we hypothesized that differences in SDF-1α expression may be responsible for the differential activity of HPMCs and a-HPMCs observed in our study, we found no evidence to support this (data not shown). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.
    International Journal of Oncology 05/2012; 41(2):476-82. DOI:10.3892/ijo.2012.1490 · 3.03 Impact Factor
  • Source
    • "BMP2 is a member of the transforming growth factor beta (TGFbeta) family, which inhibits growth in gliomas [49] and medulloblastomas [50], whereas the latter tumors are able to secrete BMP2 themselves. On the other hand, BMP2 is linked to angiogenesis [51, 52], which is consistent with the glioblastoma being one of the most vascularized tumors in man [53]. The role of BMP2 in glioblastoma has not yet been elucidated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p < 0.0001, Fischer's exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p < 0.0001, Fischer's exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.
    Journal of Neuro-Oncology 03/2011; 102(1):71-80. DOI:10.1007/s11060-010-0284-8 · 3.07 Impact Factor
Show more


9 Reads