A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

Farnsworth, Rae H.; Karnezis, Tara; Shayan, Ramin; Matsumoto, Masataka; Nowell, Cameron J.; Achen, Marc G.; Stacker, Steven A.

doi:10.1158/0008-5472.can-11-0200

Cited by 61 publications

(46 citation statements)

References 51 publications

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“…In addition, carboxypeptidase A4 shows a pronounced down-regulation (FPKM 67 to 1). The cytokine bone morphogenetic protein 4 (BMP4), known to suppress the proliferation of cancer cells and to stimulate cell migration and invasion (18,19), is also down-regulated. These proteins are interesting targets for further studies aimed at identifying potential markers for metastatic capabilities.…”

Section: Few Genes Show Altered Expression Upon Mutant Ras Transformamentioning

confidence: 99%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

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Section: Few Genes Show Altered Expression Upon Mutant Ras Transformamentioning

confidence: 99%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…BMPs function through conserved type I and type II transmembrane receptors and Smad-dependent and -independent pathways, to regulate a range of biological processes in a highly context-dependent manner (1,(3)(4)(5). Disruption of these pathways can lead to various diseases including cancer (6).…”

Section: Introductionmentioning

confidence: 99%

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

Wang

Huang

Baowei

et al. 2012

Molecular Medicine Reports

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Abstract. The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-β-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.

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“…Thus, BMP4 regulation of VEGF appears cell and tissue specific. BMP4 regulation of angiogenesis in developing tissues and during neoplastic transformation appears to be via activation of SMAD1/5/8 and downstream activation of VEGF family and its receptors (Lowery and de Caestecker, 2010;Farnsworth et al, 2011).…”

Section: B Bmp Effects On Leptomeningeal and Other Central Nervous mentioning

confidence: 99%

Transforming Growth Factor-beta Superfamily in Meningiomas: Targets for Novel Therapy in eningiomas

Johnson

2015

IJN

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Meningiomas are central nervous system tumors with a high recurrence rate. In the absence of effective chemotherapies, inoperable, recurrent and metastatic tumors remain a therapeutic challenge. Members of the TGF- super-family play an integral role in the development, progression and metastases of many malignancies yet may be underappreciated participants in the biology of meningiomas. This paper reviews the common abnormalities in TGF- or BMP signaling in neoplasias with a focus on meningiomas. Sites of potential targeting for new chemotherapies are also noted.

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A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

Cited by 61 publications

References 51 publications

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

Transforming Growth Factor-beta Superfamily in Meningiomas: Targets for Novel Therapy in eningiomas

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