The role of tumor metastasis suppressors in cancers of breast and prostate

Furuta, Eiji

doi:10.2741/2013

Cited by 13 publications

(14 citation statements)

References 63 publications

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“…Immunohistochemical analysis of human prostate tumor samples revealed that the KAI1 expression was downregulated in >70% of the primary tumors (4). Similar results were also observed in other types of tumors, including lung, breast, pancreatic, colon, bladder, ovarian, hepatocellular carcinoma, and melanoma (1,5). KAI1 gene expression is correlated with poor survival in patients with these types of cancers.…”

supporting

confidence: 71%

Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression

2007

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Tumor metastases suppressor protein KAI1/CD82 is capable of blocking the tumor metastases without affecting the primary tumor formation, and its expression is significantly downregulated in many types of human cancers. However, the exact molecular mechanism of the suppressor function of KAI1 remains elusive. Evidence from our laboratory supports a model in which tumor cells dislodge from the primary tumor and intravasate into the blood or lymphatic vessels followed by attachment to the endothelial cell surface whereby KAI1 interacts with the Duffy antigen receptor for chemokines (DARC) protein. This interaction transmits a senescent signal to cancer cells expressing KAI1, whereas cells that lost KAI1 expression can proliferate, potentially giving rise to metastases. Our model of the mechanism of action of KAI1 shows that metastasis suppressor activity can be dependent on interaction with host tissue and explains how KAI1 suppresses metastasis without affecting primary tumor formation. Taken together, in vitro and in vivo studies identify the KAI1-DARC interaction as a potential target for cancer therapy. KAI1 Blocks Metastases without Affecting Primary Tumor FormationWhen cancer is diagnosed, the most critical question is whether the disease is localized or has it already disseminated to other parts of the body. Unfortunately, the majority of patients already have a clinically undetectable metastatic disease at the time of a visit to the clinic, and >90% of cancer patients ultimately succumb to sequelae of metastatic disease. Following primary tumor formation, a population of tumor cells can acquire molecular and cellular changes, which enable cancer to spread to distant sites. These include invasive phenotype that results in the loss of cell-cell adhesion and cell-extracellular matrix adhesion followed by proteolytic degradation of the matrix. Additional changes are needed in order for cells to intravasate into neighboring blood and lymphatic vessels and disseminate through the circulation. Those cells that survive in the circulation are arrested at distant organ sites, extravasate, and lodge at the secondary sites, where the cells must also proliferate and colonize for successful metastasis. The molecular mechanism(s) regulating acquisition of metastatic ability remains poorly understood despite the urgent need for development of novel treatment options for patients with metastatic disease. The discovery of a series of metastasis suppressor genes in the past decade has shed new light on many crucial aspects of this intricate biological process. The metastases suppressor genes and their encoded proteins, by definition, suppress the process of metastasis without affecting tumorigenesis. To date, more than a dozen of these genes have been identified and include nm23, KAI1, Kiss1, BRMS1, MKK4, RhoGDI2, RKIP, Drg-1, CRSP3, SSeCKs, TXNIP/VDUP-1, Claudin-4, and RRM1 (1).The KAI1 gene was originally isolated as a prostate-specific tumor metastasis suppressor gene using the microcell-mediated chromosome transf...

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confidence: 71%

Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression

2007

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“…Cell motility and invasiveness are defining characteristics of advanced tumors, which enable tumor cells to migrate into adjacent tissues or through basement membranes and extracellular matrices. [8][9][10][11][12] Multidrug resistance in cancer is associated with an enhanced drug efflux, where ATP binding cassette (ABC) transporter proteins play an important role. 13,14 The epidermal growth factor (EGF) receptor (EGFR) pathway is a clear example of a signal transduction pathway that has been associated with development, progression, and resistance to treatment with cytotoxic drugs of a number of human solid tumors including breast.…”

Section: Introductionmentioning

confidence: 99%

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

García¹,

Franklin²,

McCubrey³

2006

Cell Cycle

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The epidermal growth factor receptor (EGFR) is important for normal development, differentiation, and cell proliferation. Deregulation of EGFR has been observed in breast cancer. EGFR and signal pathways activated by these receptors have been associated with an advanced tumor stage and a poor clinical prognosis in breast cancer; however, the precise mechanisms responsible for this process are still not known. Here we show that treatment of MCF-7 breast cancer cells with EGF activated Akt and ERK, induced morphological changes, and increased cell motility. In addition, the constitutive expression of Raf-1 and the use of a MEK inhibitor demonstrated the participation of the Raf/MEK/ERK pathway in these processes. Importantly we detected that EGF induced MRP-1, 3, 5 and 7 gene expression and an increase in MRP1 promoter activity. In conclusion, treatment of MCF-7 breast cancer cells with EGF, in the absence of other growth factors, resulted in activation of EGFR signal transduction pathways; which were related with cell motility and drug resistance.

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“…Despite the advances in cancer therapies and the understanding that metastasis is a selective, nonrandom and inefficient process, it significantly contributes to morbidity and mortality of cancer patients and is a major challenge yet to be met in cancer therapeutics (1)(2)(3)(4). Increased cell motility is one of the early and essential phenotype of metastatic cancers.…”

mentioning

confidence: 99%

Loss-of-function screening by randomized intracellular antibodies: Identification of hnRNP-K as a potential target for metastasis

Inoue

Sawata

Taira

et al. 2007

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

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We have developed a loss-of-function screening system on the basis of intracellular expression of single domain antibodies. We demonstrate its use in identification of potential targets of metastasis of human cancerous cells. Randomized intracellular antibodies were expressed in highly metastatic cells, and a derivative pool of cells with loss of migration phenotype in chemotaxis assay was isolated. Isolation of antibodies from cells with loss of migration phenotype and identification of their target proteins revealed the involvement of the heterogeneous nuclear ribonucleoprotein K (hnRNP-K), a multifunctional signaling protein, in metastasis. Furthermore, we found that the cytoplasmic accumulation of hnRNP-K is crucial for its role in metastasis. The results demonstrate (i) the advantages of our functional interference screening over the gene-knockouts and genesilencing, (ii) hnRNP-K as a potential target of metastasis, and (iii) a potential anti-metastasis peptide validated in in vitro cell migration assays.heterogeneous nuclear ribonucleoprotein K ͉ randomized antibodies ͉ functional screening ͉ cytoplasmic accumulation ͉ antimetastasis M etastasis is a complex phenomenon that involves an array of genetic changes and coordination of many positive and negative factors leading to motile cells that can penetrate into and travel through the bloodstream forming secondary tumors elsewhere in the body. Despite the advances in cancer therapies and the understanding that metastasis is a selective, nonrandom and inefficient process, it significantly contributes to morbidity and mortality of cancer patients and is a major challenge yet to be met in cancer therapeutics (1-4). Increased cell motility is one of the early and essential phenotype of metastatic cancers. Although it has been demonstrated to involve concerted reorganization of the actin cytoskeleton that regulates cell shape, and motility through spatiotemporal activation of Rho-family GTPases (5-9), the molecular mechanisms and its upstream regulators, the potential targets of metastasis, have not been sufficiently defined (10). Amongst a large variety of approaches that can be adopted to identify ''metastasis genes,'' we chose to employ a functional interference of proteins by expression of intracellular antibodies, also called as ''specific functional ablators'' and ''functional therapeutical molecules'' (11-13). We anticipated that the functional interference may serve as a milder and finer approach to reveal biological complexities and pathways that cannot be resolved by gene-knockouts and genesilencing strategies that challenge structural integrity of cells.We constructed a randomized intracellular antibody library (iAb-lib) on the basis of the single heavy-chain small antigenbinding fragments (VHH) of camel antibody. By employing iAb-lib against cell migration of highly malignant human fibrosarcoma, we obtained a derivative cell population in which cell migration was compromised. Cloning and characterization of antibodies from the derivative nonmigrating...

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The role of tumor metastasis suppressors in cancers of breast and prostate

Cited by 13 publications

References 63 publications

Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression

Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

Loss-of-function screening by randomized intracellular antibodies: Identification of hnRNP-K as a potential target for metastasis

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