Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation

Beppu, Hideyuki; Mwizerwa, Olive; Beppu, Yuko; Dattwyler, Matthew; Lauwers, Gregory Y.; Bloch, Kenneth D.; Goldstein, Allan M.

doi:10.1038/sj.onc.1210720

Cited by 71 publications

(60 citation statements)

References 27 publications

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“…However, different results are seen when BMP signaling is examined in vivo. Disruption of BMPR2, the receptor for BMP2, 4, and 7, leads to epithelial hyperplasia and formation of polyps in the colon (22) and to enhanced metastasis in mice transgenic for MMTV-PyMT (23). Consistent with this, expression of constitutively active BMPR1B in mammary tumor cells suppresses metastasis to lung (24).…”

Section: Introductionsupporting

confidence: 54%

BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

et al. 2014

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The TGFb growth factor family member BMP4 is a potent suppressor of breast cancer metastasis. In the mouse, the development of highly metastatic mammary tumors is associated with an accumulation of myeloid-derived suppressor cells (MDSC), the numbers of which are reduced by exogenous BMP4 expression. MDSCs are undetectable in na€ ve mice but can be induced by treatment with granulocyte colony-stimulating factor (G-CSF/Csf3) or by secretion of G-CSF from the tumor. Both tumor-induced and G-CSF-induced MDSCs effectively suppress T-cell activation and proliferation, leading to metastatic enhancement. BMP4 reduces the expression and secretion of G-CSF by inhibiting NF-kB (Nfkb1) activity in human and mouse tumor lines. Because MDSCs correlate with poor prognosis in patients with breast cancer, therapies based on activation of BMP4 signaling may offer a novel treatment strategy for breast cancer. Cancer Res; 74(18); 5091-102. Ó2014 AACR.

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Section: Introductionsupporting

confidence: 54%

BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

et al. 2014

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“…It could either be a serendipitous finding, or a genuine indication of altered epithelial -mesenchymal interactions within a subset of tumours. In these tumours, hypoxia-driven metabolic and cell biological changes could hypothetically alter the tumour stroma toward an environment that can facilitate cancer progression, along multiple routes, leading to an enhanced proliferation or survival of tumour epithelial cells (Beppu et al, 2008). Under hypoxic conditions, the tumour stroma can select for the propagation of certain subclones of cancer cells that are optimally endowed for tumour progression.…”

Section: Discussionmentioning

confidence: 99%

Poorer outcome in stromal HIF-2α- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis

et al. 2008

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Stromal expression of hypoxia inducible factor 2a (HIF-2a) and carbonic anhydrase 9 (CA9) are associated with a poorer prognosis in colorectal cancer (CRC). Tumour cell death, regulated by a hypoxic stromal microenvironment, could be of importance in this respect. Therefore, we correlated apoptosis, TP53 mutational status and BNIP3 promoter hypermethylation of CRC cells with HIF-2a-and CA9-related poor outcome. In a series of 195 CRCs, TP53 mutations in exons 5 -8 were analysed by direct sequencing, and promoter hypermethylation of BNIP3 was determined by methylation-specific PCR. Expressions of HIF-2a, CA9, p53, BNIP3 and M30 were analysed immunohistochemically. Poorer survival of HIF-2a and CA9 stromal-positive CRCs was associated with wild-type TP53 (P ¼ 0.001 and P ¼ 0.0391), but not with BNIP3 methylation. Furthermore, apoptotic levels were independent of the TP53 status, but lower in unmethylated BNIP3 CRCs (P ¼ 0.004). It appears that wild-type TP53 in CRC cells favours the progression of tumours expressing markers for hypoxia in their stroma, rather than in the epithelial compartment. Preserved BNIP3 function in CRC cells lowers apoptosis, and may thus be involved in alternative cell death pathways, such as autophagic cell death. However, BNIP3 silencing in tumour cells does not impact on hypoxia-driven poorer prognosis. These results suggest that the biology of CRC cells can be modified by alterations in the tumour microenvironment under conditions of tumour hypoxia.

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“…Conditional inactivation of the bone morphogenic protein Type II receptor in the stroma increases the myofibroblast cell population, causing epithelial hyperplasia throughout the colon. 68 Furthermore, loss of TGF-b responsiveness in fibroblast specific protein-1-positive fibroblasts, by conditional inactivation of the TGF-b Type II receptor, resulted in an increase of scatter factor/hepatocyte growth factor (SF/HGF)-secreting stromal fibroblasts causing intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach. 69 In another model, lowering Foxf gene dosage by inactivation of the Foxf1 and Foxf2 mesenchymal forkhead transcription factors results in accumulation of Wnt5a secreting a-SMA positive myofibroblasts.…”

Section: Characterization and Origin Of A Myofibroblastmentioning

confidence: 99%

Stromal myofibroblasts are drivers of invasive cancer growth

Wever¹,

Demetter²,

Mareel³

et al. 2008

Intl Journal of Cancer

620

600

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Tissue integrity is maintained by the stroma in physiology. In cancer, however, tissue invasion is driven by the stroma. Myofibroblasts and cancer-associated fibroblasts are important components of the tumor stroma. The origin of myofibroblasts remains controversial, although fibroblasts and bone marrow-derived precursors are considered to be the main progenitor cells. Myofibroblast reactions also occur in fibrosis. Therefore, we wonder whether nontumorous myofibroblasts have different characteristics and different origins as compared to tumor-associated myofibroblasts. The mutual interaction between cancer cells and myofibroblasts is dependent on multiple invasive growth-promoting factors, through direct cell-cell contacts and paracrine signals. Since fibrosis is a major side effect of radiotherapy, we address the question how the main methods of cancer management, including chemotherapy, hormonotherapy and surgery affect myofibroblasts and by inference the surrogate endpoints invasion and metastasis.

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Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation

Cited by 71 publications

References 27 publications

BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

Poorer outcome in stromal HIF-2α- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis

Stromal myofibroblasts are drivers of invasive cancer growth

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