Metastasis suppressor

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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] [2] 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. [3]

Contents

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. [4]

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. [4]

Clinical applications

Metastasis suppressors can potentially serve as prognostic markers, therapeutic targets and predictors for treatment response. [4]

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. [4]

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. [4]

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. [4]

Genes

Genes for about a dozen metastasis-suppressing proteins are known in humans and other animals, including BRMS1, CRSP3, DRG1, KAI1, SDPR, KISS1, NM23 and various TIMPs. [5] [6] [7] 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. [3] [11] These proteins are different from ones that act to suppress tumor growth. [12]

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

<span class="mw-page-title-main">Maspin</span> Protein-coding gene in the species Homo sapiens

Maspin is a protein that in humans is encoded by the SERPINB5 gene. This protein belongs to the serpin superfamily. SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues. Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis. However, a subsequent study using viral transduction as a method of gene transfer was not able to reproduce the original findings and found no role for maspin in tumour biology. Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype. These data are consistent with the observation that maspin is not expressed in early embryogenesis. The precise molecular function of maspin is thus currently unknown.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">RASSF1</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.

<span class="mw-page-title-main">NME1</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene. It is thought to be a metastasis suppressor.

<span class="mw-page-title-main">NME2</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate kinase B is an enzyme that in humans is encoded by the NME2 gene.

<span class="mw-page-title-main">DLC1</span> Protein-coding gene in the species Homo sapiens

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

<span class="mw-page-title-main">MAGEA4</span> Protein-coding gene in humans

Melanoma-associated antigen 4 is a protein that in humans is encoded by the MAGEA4 gene.

<span class="mw-page-title-main">BRMS1</span> Protein-coding gene in the species Homo sapiens

Breast cancer metastasis suppressor 1 is a protein that in humans is encoded by the BRMS1 gene.

<span class="mw-page-title-main">TCF21 (gene)</span> Protein-coding gene in the species Homo sapiens

Transcription factor 21 (TCF21), also known as pod-1, capsuling, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">EMP3</span> Protein-coding gene in the species Homo sapiens

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.

<span class="mw-page-title-main">SDPR</span> Protein-coding gene in the species Homo sapiens

Cavin-2 or Serum deprivation-response protein (SDPR) is a protein that in humans is encoded by the SDPR gene. Cavin-2 is highly expressed in a variety of human endothelial cells.

<span class="mw-page-title-main">MTDH</span> Protein-coding gene in the species Homo sapiens

Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene.

<span class="mw-page-title-main">NME4</span> Protein-coding gene in the species Homo sapiens

Non-metastatic cells 4, protein expressed in, also known as NME4, is a protein which in humans is encoded by the NME4 gene.

mir-205 Micro RNA involved in the regulation of multiple genes

In molecular biology miR-205 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. They are involved in numerous cellular processes, including development, proliferation, and apoptosis. Currently, it is believed that miRNAs elicit their effect by silencing the expression of target genes.

mir-31

miR-31 has been characterised as a tumour suppressor miRNA, with its levels varying in breast cancer cells according to the metastatic state of the tumour. From its typical abundance in healthy tissue is a moderate decrease in non-metastatic breast cancer cell lines, and levels are almost completely absent in mouse and human metastatic breast cancer cell lines. Mir-31-5p has also been observed upregulated in Zinc Deficient rats compared to normal in ESCC and in other types of cancers when using this animal model. There has also been observed a strong encapsulation of tumour cells expressing miR-31, as well as a reduced cell survival rate. miR-31's antimetastatic effects therefore make it a potential therapeutic target for breast cancer. However, these two papers were formally retracted by the authors in 2015.

Anticancer genes exhibit a preferential ability to kill cancer cells while leaving healthy cells unharmed. This phenomenon is achieved through various processes such as apoptosis following a mitotic catastrophe, necrosis, and autophagy. In the late 1990s, extensive research in the field of cancer cells led to the discovery of anticancer genes. Mutations in these genes due to base substitutions leading to insertions, deletions, or alterations in missense amino acids can cause frameshifts, thereby altering the protein. A change in gene copy number or rearrangements is also essential for deregulating these genes. The loss or alteration of these anticancer genes due to mutations or rearrangements may lead to the development of cancer.

References

  1. 1 2 3 4 Olle, David (September 9, 2009). "Metastasis Suppressors". Suite 101.{{cite web}}: Missing or empty |url= (help)[ self-published source? ]
  2. ↑ Gkountela, Sofia; Aceto, Nicola (2016-07-26). "Stem-like features of cancer cells on their way to metastasis". Biology Direct. 11: 33. doi: 10.1186/s13062-016-0135-4 . ISSN   1745-6150. PMC   4960876 . PMID   27457474.
  3. 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.
  4. 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.
  5. ↑ Ozturk, Sait; Papageorgis, Panagiotis; Wong, Chen Khuan; Lambert, Arthur W.; Abdolmaleky, Hamid M.; Thiagalingam, Arunthathi; Cohen, Herbert T.; Thiagalingam, Sam (2016). "SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis". Proceedings of the National Academy of Sciences. 113 (3): 638–643. Bibcode:2016PNAS..113..638O. doi: 10.1073/pnas.1514663113 . PMC   4725521 . PMID   26739564.
  6. ↑ 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.
  7. ↑ Jackson, Paul (2007). New Developments in Metastasis Suppressor Research. Nova Publishers. ISBN   978-1-60021-603-9.[ page needed ]
  8. ↑ Ozturk, Sait; Papageorgis, Panagiotis; Wong, Chen Khuan; Lambert, Arthur W.; Abdolmaleky, Hamid M.; Thiagalingam, Arunthathi; Cohen, Herbert T.; Thiagalingam, Sam (2016). "SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis". Proceedings of the National Academy of Sciences. 113 (3): 638–643. Bibcode:2016PNAS..113..638O. doi: 10.1073/pnas.1514663113 . PMC   4725521 . PMID   26739564.
  9. ↑ Ozturk, Sait; Papageorgis, Panagiotis; Wong, Chen Khuan; Lambert, Arthur W.; Abdolmaleky, Hamid M.; Thiagalingam, Arunthathi; Cohen, Herbert T.; Thiagalingam, Sam (2016). "SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis". Proceedings of the National Academy of Sciences. 113 (3): 638–643. Bibcode:2016PNAS..113..638O. doi: 10.1073/pnas.1514663113 . PMC   4725521 . PMID   26739564.
  10. ↑ Chong, L. D. (2016). "Suppressing cancer spread". Science. 351 (6271): 351–352. Bibcode:2016Sci...351R.351C. doi: 10.1126/science.351.6271.351-g .
  11. ↑ 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.
  12. ↑ 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.

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