Metastasis suppressors genes in cancer

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• 作者：Lewis J. Stafford ; Kedar S. Vaidya ; Danny R. Welch
• 关键词：Cancer ; Metastasis ; Metastasis suppressor ; Signaling ; Tumor ; BRMS1 ; Cadherins ; CD44 ; DLC1 ; Drg1 ; Gelsolin ; KAI1 ; KISS1 ; MKK4 ; Nm23 ; RhoGDI2 ; RKIP ; RRM1 ; SSeCKS
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2008
• 期刊代码：127_13572725
• 类别：med
• 出版时间：2008
• 卷：40
• 期：5
• 页码：874-891
• 文件大小：629 K

摘要

We performed MEDLINE searches and manual bibliographic reviews on the specific steps of metastasis, including growth at the secondary site. In addition, we performed a comprehensive literature review to identify genes fitting the classic definition of a metastasis suppressor gene. The literature was also searched to assess the status of each gene in clinical cancer and evaluate functional support for the potential involvement of each gene in regulating growth at the secondary site.

Results

Clinical studies in prostate cancer and other cancer types suggest that dissemination to the secondary site is often an early clinical event. However, not all patients with tumor cells at the secondary site have overt metastatic lesions even in the absence of therapy, suggesting that growth at the secondary site may be highly inefficient. Complimentary approaches have allowed researchers to document and quantify the inefficiency of cancer cell growth at the secondary site. Regarding the mechanism of growth control, many studies support a role for the interaction of a cancer cell and the microenvironment at the secondary site influencing whether growth into metastasis may occur. The 7 genes that suppress metastasis without affecting primary tumor growth that have been identified are KAI1, CD44, mitogen activated protein kinase (MAPK) kinase 4, nm23-H1, nm23-H2, KiSS1 and BrMS1. Three of these genes (KAI1, CD44 and MAPK kinase 4) act as metastasis suppressor genes of prostate cancer, while the remainder have yet to be tested in this cancer type. Loss of expression has been demonstrated for most of these genes during the clinical progression of prostate cancer to metastasis. MAPK kinase 4 and KiSS1 appear to suppress metastasis by inhibiting cancer cell growth at the secondary site. Interestingly many metastasis suppressor genes have common roles in growth control, adhesion and cytoskeletal reorganization, suggesting a common mechanism of metastasis suppression. Proposed candidate pathways include signaling through Src kinase and Rac GTPase.

Conclusions

The findings discussed support growth at the secondary site as a clinical target for metastasis treatment and prevention. Metastasis suppressor genes may offer valuable mechanistic insight for guiding specific therapeutic strategies, which may include drug induced reactivation of metastasis suppressor genes and their signaling pathways. Clinical assessment of metastasis suppressor gene product status in disseminated cancer cells may improve the accuracy of predicting the prognosis in patients with clinically localized disease.