BMP Signaling Promotes the Growth of Primary Human Colon Carcinomas in vivo

Department of Genetic Medicine and Development, University of Geneva School of Medicine, 8242 CMU, 1 rue Michel Servet, CH-1211 Geneva, Switzerland.
Journal of Molecular Cell Biology (Impact Factor: 6.77). 12/2010; 2(6):318-32. DOI: 10.1093/jmcb/mjq035
Source: PubMed


Human colon carcinomas (CCs) represent a growing worldwide problem. One of the pathways that has been negatively implicated
in the genesis of CCs is triggered by bone morphogenetic protein (BMP) ligands, which activate BMP receptors leading to the
function of SMAD proteins in the nucleus. BMP signaling is altered in familial human polyposis, and mice with compromised
BMP signaling in the intestine develop tumors. Here, we have re-evaluated the presence and roles of BMP signaling in advanced
sporadic human CCs, using both primary tumors and established cell lines, and directly modulating BMP pathway activity in
a cell-autonomous manner using constitutively active and dominant-negative BMP receptor Ib forms. We find evidence for active
endogenous BMP signaling in all primary CC samples and for its role in promoting primary CC tumor growth and CC cell survival
and proliferation in vivo in xenografts. In vitro, we also document autonomous and non-autonomous effects of enhanced BMP receptor activity on gap closure in culture, suggesting
possible roles in invasion. Caution should thus be exerted in trying to augment or restore its activity for therapeutic purposes.
In contrast, we raise the possibility that blockade of BMP signaling might have beneficial effects against at least a subset
of advanced colon cancers.

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    • "Consistent with our findings are previous reports in which BMP2, BMP3 or BMP7 were shown to have growth-suppressive activities in colon cancer cells (16–18), although the expression of BMP4 and BMP7 was found to correlate with a worse prognosis (19,20). Notably, a more recent report showed that BMP signaling promotes the growth of primary human colon cancer in vivo and the investigators proposed that blockade of BMP signaling may have beneficial effects against at least a subset of advanced colon cancers (21). Nonetheless, studies have revealed that genetic variations in the BMP signaling pathway may be associated with the etiology, survival and/or prognosis of colon and rectal cancer (18,47–49). "
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    ABSTRACT: Colorectal cancer (CRC) is one of the most deadly cancers worldwide. Significant progress has been made in understanding the molecular pathogenesis of CRC, which has led to successful early diagnosis, surgical intervention and combination chemotherapy. However, limited therapeutic options are available for metastatic and/or drug-resistant CRC. While the aberrantly activated Wnt/β-catenin pathway plays a critical initiating role in CRC development, disruption of the bone morphogenetic protein (BMP) pathway causes juvenile polyposis syndrome, suggesting that BMP signaling may play a role in CRC development. However, conflicting results have been reported concerning the possible roles of BMP signaling in sporadic colon cancer. Here, we investigated the effect of BMP2 on the proliferation, migration, invasiveness and tumor growth capability of human CRC cells. Using an adenovirus vector that overexpresses BMP2 and the piggyBac transposon-mediated stable BMP2 overexpression CRC line, we found that exogenous BMP2 effectively inhibited HCT116 cell proliferation and colony formation. BMP2 was shown to suppress colon cancer cell migration and invasiveness. Under a low serum culture condition, forced expression of BMP2 induced a significantly increased level of apoptosis in HCT116 cells. Using a xenograft tumor model, we found that forced expression of BMP2 in HCT116 cells suppressed tumor growth, accompanied by decreased cell proliferation activity. Taken together, our results strongly suggest that BMP2 plays an important inhibitory role in governing the proliferation and aggressive features of human CRC cells.
    Oncology Reports 07/2014; 32(3). DOI:10.3892/or.2014.3308 · 2.30 Impact Factor
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    • "The etiology of colorectal cancer is unclear, and early diagnosis is difficult (7). Elucidation of the mechanisms of oncogenesis in colorectal cancer mainly relies on animal models (8). "
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    ABSTRACT: Previous studies have shown that disruption of the bone morphogenetic protein (BMP) signaling pathway is an important cause of intestinal cancer in human and animal models. Thus, the purpose of this study was to construct a Balb/C model of colorectal polyps. Pregnant mice at 9.5 days gestation were injected via the tail vein with the pSES-Si BMP4 plasmid bearing a fluorochrome (DsRed) reporter, in order to silence the BMP4 gene in the first generation (F1); this group of mice was named the pSES-BMP4 group Intestinal fluorescence was detected at 1-, 4- and 8-week‑old F1 mice, and reverse transcription-polymerase chain reaction (RT-PCR) and western-blotting assays were used to determine changes in the expression of BMP4. A dissecting microscope and hematoxylin and eosin (H&E) staining were used to observe the cell morphology and appearance of the polyps. DsRed fluorescence was observed in the intestines of 1-week-old F1 mice of the pSES-BMP4 group. BMP4 expression at the mRNA and protein level was reduced in 1-, 4- and 8-week-old F1 mice (P<0.05). However, the level of Smad4 mRNA was only reduced in 8-week-old F1 mice (P<0.05). Multiple hyperplasic polyps emerged in the colon and rectum of the intestines of 4-week-old F1 mice in the pSES-BMP4 group. The size of colorectal polyps increased at 8 weeks, when vessels and polyp pedicles became apparent. In conclusion, silencing of the BMP4 gene using transplacental RNAi injection can induce formation of colorectal polyps in mice.
    Molecular Medicine Reports 05/2014; 10(1). DOI:10.3892/mmr.2014.2216 · 1.55 Impact Factor
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    • "It is a conventional way to apply terms 'oncogene' or 'tumor suppressor gene' to particular genes for their tumorigenic potential . However, a number of these genes have showed variable roles in different kinds of tumors or during different stages of cancer development (Quigley and Balmain, 2009; Lorente-Trigos et al., 2010). Trp53 is a well-known tumor suppressor gene, of which mutations occur in approximately half of all human cancers (Levine and Oren, 2009). "
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    ABSTRACT: Many of oncogenes and tumor suppressor genes have been found to exert variable and even opposing roles in different kinds of tumors or at different stages of cancer development. Here we showed that tumorigenic potential of mouse embryonic carcinoma P19 cells cultured in adherent plates (attached-P19-cells) was suppressed by a chemotherapeutic agent, 5-aza-2'-deoxycytidine (ZdCyd), whereas the higher pro-tumorigenicity of P19 cells growing in suspension (detached-P19-cells) was generated by the ZdCyd treatment. Surprisingly, p53 activity was highly up-regulated by ZdCyd in both growing conditions. By our developed computational approaches, we revealed that there was a significant enrichment of apoptotic pathways in the ZdCyd-induced p53-dominant gene-regulatory network in attached P19 cells, whereas the pro-survival genes were significantly enriched in the ZdCyd-induced p53 network in detached P19 cells. The protein-protein interaction network of the ZdCyd-treated detached P19 cells was significantly different from that of ZdCyd-treated attached P19 cells. On the other hand, inhibition of p53 expression by siRNA suppressed the ZdCyd-induced tumorigenesis of detached P19 cells, suggesting that the ZdCyd-activated p53 plays oncogenic function in detached P19 cells. Taken together, these results indicate a context-dependent role for the ZdCyd-activated p53-dominant network in tumorigenesis.
    Journal of Molecular Cell Biology 06/2012; 4(4):197-206. DOI:10.1093/jmcb/mjs029 · 6.77 Impact Factor
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