Metastasis suppressor

A metastasis suppressor is a protein that acts to slow or prevent metastases (secondary tumors) from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths.[1] Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.[2]

Background

The treatment of cancer usually aims to destroy and/or stop the growth of the primary tumor. Major improvements in the methods of surgery, radiation and chemotherapy have taken place, but corresponding improvements in patient survival have not always followed. Treatments that focus on the primary cancer typically do not address metastasis.[1]

Metastasis suppressors act by different mechanisms than tumor suppressors and do not affect primary tumors. Tumor suppressors, however, also inhibit metastasis, since metastasis is dependent upon tumorigenicity.[1]

Metastasis suppressors were first identified using microcell-mediated chromosome transfer (MMCT), which introduces chromosomes into intact recipient cells. Chromosomes 1, 6, 7, 8, 10, 11, 12, 16 and 17 harbor metastasis suppressor genes.[3]

MicroRNAs (miRNAs) are a class of gene regulators that bind the 3′ untranslated regions of target messenger RNAs, leading to either suppression of their translation or acceleration of their degradation. In cell MDA-MB-231 and its metastatic variant, six miRNAs displayed lower expression in metastatic cells. Among them, miR-335 and miR-126 suppress metastasis without affecting primary tumor growth. miR-335 targets multiple pathways, including SOX4, MERTK, PTPRN2 and TNC, which contribute to metastasis-suppression. miR-335 expression is correlated with metastasis-free survival in clinical breast cancer.[3]

Clinical applications

Metastasis suppressors can potentially serve as prognostic markers, therapeutic targets and predictors for treatment response.[3]

Prognosis

High NM23 expression is correlated with good prognosis in multiple tumor types, including breast cancer. KAI1, PEBP1 and RECK expression correlate with improved survival in multiple tumor types, including colorectal cancer. High expression of CTGF is correlated with improved survival in colorectal cancer, non-small cell lung carcinoma and gallbladder cancer, but the correlation is reversed in esophageal cancer and glioma.[3]

Targets

Patients with NM23 -positive ovarian cancer respond better to cisplatin than patients with NM23-negative tumors and esophageal squamous cell carcinoma. NM23 expression is correlated with increased survival after cisplatin treatment following surgery.[3]

Unlike tumor suppressors, most metastasis suppressors are downregulated in clinical tumor samples rather than mutated. Activation of these metastasis suppressors can potentially block metastasis and improve survival. The promoter region of NM23 contains glucocorticoid response elements that can elevate NM23 expression. Treating human breast cancer cells with dexamethasone medroxyprogesterone acetate (MPA) increases NM23 expression.[3]

Genes

Genes for about a dozen metastasis-suppressing proteins are known in humans and other animals, including BRMS1, CRSP3, DRG1, KAI1, KISS1, NM23 and various TIMPs.[4][5] Most act by altering aspects of signal transduction.

Impact

Metastasis suppressor genes may offer 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 prognosis accuracy in patients with clinically localized disease.[6][2] These proteins are different from ones that act to suppress tumor growth.[7]

References

  1. 1 2 3 4 Olle, David (September 9, 2009). "Metastasis Suppressors". Suite 101.
  2. 1 2 Sobel, Mark E. (1990). "Metastasis Suppressor Genes". Journal of the National Cancer Institute 82 (4): 267–76. doi:10.1093/jnci/82.4.267. PMID 2405170.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Yan, Jinchun; Yang, Qin; Huang, Qihong (2013-03-01). "Metastasis Suppressor Genes". Histology and histopathology 28 (3): 285–292. ISSN 0213-3911. PMC 3910084. PMID 23348381.
  4. ↑ Shevde, Lalita A.; Welch, Danny R. (2003). "Metastasis suppressor pathways—an evolving paradigm". Cancer Letters 198 (1): 1–20. doi:10.1016/S0304-3835(03)00304-5. PMID 12893425.
  5. ↑ Jackson, Paul (2007). New Developments in Metastasis Suppressor Research. Nova Publishers. ISBN 978-1-60021-603-9.
  6. ↑ Kauffman, Eric C.; Robinson, Victoria L.; Stadler, Walter M.; Sokoloff, Mitchell H.; Rinker-Schaeffer, Carrie W. (2003). "Metastasis Suppression: The Evolving Role of Metastasis Suppressor Genes for Regulating Cancer Cell Growth at the Secondary Site". The Journal of Urology 169 (3): 1122–33. doi:10.1097/01.ju.0000051580.89109.4b. PMID 12576866.
  7. ↑ Yoshida, Barbara A.; Sokoloff, Mitchell M.; Welch, Danny R.; Rinker-Schaeffer, Carrie W. (2000). "Metastasis-Suppressor Genes: a Review and Perspective on an Emerging Field". Journal of the National Cancer Institute 92 (21): 1717–30. doi:10.1093/jnci/92.21.1717. PMID 11058615.

Further reading

External links

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