RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis

Hakem, Anne; Sanchez-Sweatman, Otto; You-Ten, Annick; Duncan, Gordon S.; Wakeham, Andrew; Khokha, Rama; Mak, Tak W.

doi:10.1101/gad.1310805

Cited by 266 publications

(239 citation statements)

References 19 publications

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“…In addition to the elucidation of the genetic program of Rho subfamily members (see Supplementary text online) and the identification of three transcriptionally regulated protein networks that are crucial for their transforming activity (E2F, c-Myc, c-Jun), one of the main results of this work is the observation that the constitutively active forms of these three GTPases trigger highly similar transcriptomal programs. This was somewhat striking as these GTPases trigger different, and sometimes antagonistic biological responses in certain cell contexts (Liu et al, 2001;Simpson et al, 2004;Wheeler and Ridley, 2004;Hakem et al, 2005). This indicates that the functional specificity of these GTPases may be established outside the transcriptional program (i.e., via the posttranscriptional activation of cellular processes) or, alternatively, that it may require additional regulatory components and/or specific cell backgrounds.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

2007

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We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5 0 -triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rhotransformed cells.

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Section: Discussionmentioning

confidence: 99%

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

2007

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“…In our study, we specifically investigated how the metastatic gene RhoC mediates vascular remodeling and cell intravasation with the assumption that RhoC amplification would increase vessel remodeling and intravasation. Surprisingly, the RhoC MDA-435 (MDA-435, breast adenocarcinoma that overexpress RhoC) cells did not show increased ability to remodel vessels or intravasate, even though they show increased invasiveness in tissues and metastasis in mice (Hakem et al, 2005). In fact, the RhoC cells randomly scattered throughout the fish tissues, but did not tightly cluster around and remodel the intersegmental vessels, which is in contrast to the low metastatic control cells.…”

Section: Role Of Rhoc In Tumor Cell Intravasationmentioning

confidence: 99%

“…Role of VEGF in RhoC-induced tumor cell intravasation Since RhoC is not involved in tumorigenesis per se, we reasoned that RhoC may be a late-activating gene that facilitates intravasation after the angiogenic switch has been triggered in advanced-stage tumors (Hakem et al, 2005). To mimic the angiogenic switch in zebrafish, we engineered the MDA-435-RhoC cells to secrete human vascular endothelial growth factor (VEGF) and injected these cells into the peritoneal cavity of 30-day-old animals.…”

Section: Role Of Rhoc In Tumor Cell Intravasationmentioning

confidence: 99%

Catch of the day: zebrafish as a human cancer model

2008

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Zebrafish are making big waves in the field of cancer research. The effect has been widespread and continues to gain speed as more and more cancer researchers ride the wave of zebrafish biology. This has been largely due to the development of transgenic and xenograft models of cancer, which recapitulate many aspects of different human cancers including lymphoblastic T-cell leukemia, pancreatic cancer, melanoma and rhabdomyosarcoma. These models are already being utilized by academia and industry to search for genetic and chemical modifiers of cancer with success. The attention has been further stimulated by the amenability of zebrafish to pharmacological testing and the superior imaging properties of fish tissues that allow visualization of cancer progression and angiogenesis in live animals. This review summarizes the current zebrafish models of cancer and discusses their utility in human cancer research and future directions in the field.

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“…Cells lacking RhoC display reduced motility and invasiveness in vitro. Moreover, when crossed to RhoC-deficient mice, transgenic mice developing metastatic breast cancer (MMTV-PymT) exhibit a significant decrease in metastasis together with increased apoptosis of disseminating cells [140]. Protease-activated receptors (PARs) constitute a family of G-protein-coupled receptors and are involved in various physiological processes.…”

Section: Genes Mediating Metastasismentioning

confidence: 99%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

209

160

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Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

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RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis

Cited by 266 publications

References 19 publications

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases

Catch of the day: zebrafish as a human cancer model

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

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