Rho-Regulatory Proteins in Breast Cancer Cell Motility and Invasion

Lin, Min; Golen, Kenneth L. van

doi:10.1023/b:brea.0000018424.43445.f3

Cited by 69 publications

(66 citation statements)

References 124 publications

(139 reference statements)

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“…1, genes with known functions whose regulation was changed in the chemotactic and migratory population of cells in the primary tumor were divided into six different functional categories based on the definitions provided by the gene-ontology consortium. 1 It was evident that among the functional categories mentioned here, the largest change was in the genes associated with the cell cycle, indicating a big change in the cell proliferation pattern of migratory cells. A detailed scrutiny of these cells showed that the genes associated with increasing cell proliferation were down-regulated and those genes associated with a reduction in cell proliferation were up-regulated.…”

Section: Resultsmentioning

confidence: 74%

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Breast Cancer Cells Isolated by Chemotaxis from Primary Tumors Show Increased Survival and Resistance to Chemotherapy

et al. 2004

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In this study, we have collected a migratory population of carcinoma cells by chemotaxis to epidermal growth factor-containing microneedles held in the primary tumor. The collected cells were subjected to microarray analysis for differential gene expression. The results show that antiapoptotic genes are up-regulated and pro-apoptotic genes are downregulated coordinately in the migratory subpopulation. Induction of apoptosis by doxorubicin, cisplatin, and etoposide in these cells demonstrates that they exhibit a lower drug-induced apoptotic index and lower cell death compared with carcinoma cells of the whole tumor. Our study indicates, for the first time, the capability of using a rat alograft model for evaluating the apoptotic status of a migratory subpopulation of tumor cells and the ability to study their resistance to chemotherapeutic agents directly. In addition, these results indicate that tumor cells that are chemotactic and migratory in response to epidermal growth factor in the primary tumor have a survival advantage over stationary tumor cells.

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Section: Resultsmentioning

confidence: 74%

“…For a tumor cell to become metastatic, it must be able to survive in the circulation and respond appropriately to new environments. This includes being able to migrate both within and beyond the primary tumor, in and out of blood and lymph vessels, and to use growth factors available at the site of metastasis for attachment and growth (1).…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Cells Isolated by Chemotaxis from Primary Tumors Show Increased Survival and Resistance to Chemotherapy

et al. 2004

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“…The formation and growth of metastases is the principal cause of death for most cancer patients, particularly those with head and neck cancer (13,14). An ever-expanding body of evidence is implicating RhoC GTPase as a critical determinant of metastasis for a variety of tumor types (1 -9).…”

Section: Discussionmentioning

confidence: 99%

RhoC GTPase Expression as a Potential Marker of Lymph Node Metastasis in Squamous Cell Carcinomas of the Head and Neck

Kleer

Teknos

Islam

et al. 2006

Clinical Cancer Research

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Purpose: Survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained unchanged for several decades due to local tumor recurrences as well as regional and distant metastases. Recent evidence has shown that RhoC GTPase is overexpressed in stages III and IV regionally metastatic SCCHN compared with stages I and II localized disease. This study evaluated the expression of RhoC in head and neck carcinoma and investigated the prognostic use of this marker on a large cohort of previously untreated patients with SCCHN. Experimental Design: Standard Western blot techniques were used to evaluate RhoC protein expression in nine established head and neck cancer cell lines and in normal oral epithelium. In vivo expression of RhoC in metastatic and nonmetastatic SCCHN was investigated using immunohistochemical analysis on a tissue microarray composed of 113 independent tumor samples. RhoC expression was analyzed as it related to clinical and pathologic variables of interest. Results: Levels of RhoC protein were increased in the SCCHN cell lines compared with normal oral epithelium.The in vivo expression of RhoC correlated with advanced clinical stage and lymph node metastases for the entire patient cohort as well as in small primary tumors (T 1 and T 2 ). Conclusions:This study is the first to examine the expression of RhoC GTPase protein in SCCHN and normal squamous epithelium. It is clear from the results that RhoC is a specific marker of lymph node metastases in patients with this challenging form of carcinoma. RhoC levels seem to identify a subset of patients with early tumor stage primary tumors and high metastatic potential that might benefit from more aggressive therapy. Through continued investigation, blockade of RhoC activity may be a potential target in the development of novel strategies for treating metastases of head and neck cancer. Squamous cell carcinoma of the head and neck (SCCHN)accounts for >95% of all head and neck malignancies and is responsible for f40,000 incident cases yearly in the United States. Unfortunately, the majority of SCCHN patients present with advanced-stage disease (stages III and IV), requiring multimodality therapy. Even with combinations of chemotherapy, radiotherapy, and surgery, cure rates are only 30% for advanced-stage disease and have remained unchanged for decades. This poor survival is due mainly to the development of local tumor recurrences as well as regional and distant metastases. Novel molecular predictors of regional and distant metastatic potential at the time of diagnosis are needed to help guide clinical therapy decisions.Many of the factors necessary to convey the metastatic phenotype to cancer cells are controlled by the members of the Ras superfamily of small GTP-binding proteins. RhoC GTPase is a member of the Ras superfamily, and its activation results in the assembly of the actin-myosin contractile filaments into focal adhesion complexes that, ultimately, lead to cell polarity and facilitate motility (1 -3). Our laboratory has d...

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“…The Rho-GTPase family consists of small 20 to 30 kDa monomeric GTP-binding proteins that bind GDP/GTP and hydrolyze GTP, leading to the activation of downstream effector molecules (22). In this signaling scheme, metastasis suppressors have been identified as upstream inhibitors of the Rho family (23), or downstream effectors (24).…”

Section: Cytoskeletal and Extracellular Matrix^related Signalingmentioning

confidence: 99%

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Rinker‐Schaeffer

O’Keefe

Welch

et al. 2006

Clinical Cancer Research

120

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Clinically and experimentally, primary tumor formation and metastasis are distinct processes -locally growing tumors can progress without the development of metastases. This observation prompted the hypothesis that the molecular processes regulating tumorigenicity and metastasis are distinguishable and could be targeted therapeutically. During the process of transformation and subsequent progression to a malignant phenotype, both genetic and epigenetic alterations alter a cell's ability to perceive and respond to signals that regulate normal tissue homeostasis. A minority of tumorigenic cells accrue the full complement of alterations that enables them to disseminate from the primary tumor, survive insults from the immune system and biophysical forces, and respond to growthpromoting and/or inhibitory signals from the distant tissues and thrive there. Identification of genes and proteins that specifically inhibit the ability of cells to form metastases (e.g., metastasis suppressors) is providing new insights into the molecular mechanisms that regulate this complex process. This review will highlight: (a) the functional identification of metastasis suppressors, (b) the signaling cascades and cellular phenotypes which are controlled or modulated by metastasis suppressors, and (c) opportunities for translation and clinical trials that are based on mechanistic studies regarding metastasis suppressors.

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Rho-Regulatory Proteins in Breast Cancer Cell Motility and Invasion

Abstract: The importance of the Rho-GTPases in cancer progression, particularly in the area of metastasis, is becoming increasingly evident. This review will provide an overview of the role of the Rho-regulatory proteins in breast cancer metastatis.

Cited by 69 publications

References 124 publications

Breast Cancer Cells Isolated by Chemotaxis from Primary Tumors Show Increased Survival and Resistance to Chemotherapy

Breast Cancer Cells Isolated by Chemotaxis from Primary Tumors Show Increased Survival and Resistance to Chemotherapy

RhoC GTPase Expression as a Potential Marker of Lymph Node Metastasis in Squamous Cell Carcinomas of the Head and Neck

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

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