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]
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]
Metastasis suppressors can potentially serve as prognostic markers, therapeutic targets and predictors for treatment response. [4]
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]
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 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.
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]
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.
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.
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.
Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.
Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the NME1 gene. It is thought to be a metastasis suppressor.
CD82, or KAI1, is a human protein encoded by the CD82 gene.
Nucleoside diphosphate kinase B is an enzyme that in humans is encoded by the NME2 gene.
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.
Breast cancer metastasis suppressor 1 is a protein that in humans is encoded by the BRMS1 gene.
PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene. PINX1 is also known as PIN2 interacting protein 1. PINX1 is a telomerase inhibitor and a possible tumor suppressor.
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.
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.
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.
Non-metastatic cells 4, protein expressed in, also known as NME4, is a protein which in humans is encoded by the NME4 gene.
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 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.
A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum.
Melanoma inhibitory activity protein 3 (MIA3), also known as transport and Golgi organization protein 1 (TANGO1), is a protein that in humans is encoded by the MIA3 gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. MIA3 localizes to the endoplasmic reticulum (ER) exit site, where it binds bulky cargo molecules such as collagens and creates mega transport carriers for the export of cargoes from the ER. This function suggests that it plays a role in assembly of extracellular matrix (ECM) and bone formation. MIA3 has been demonstrated to contribute to both tumor suppression and progression. The MIA3 gene also contains one of 27 loci associated with increased risk of coronary artery disease.. A TANGO1 like protein called TALI is expressed in liver and intestine and shown to be required for the export of bulky very Low density lipoproteins (VLDL) and chylomicrons. TANGO1 and TALI assemble into rings around COPII coats and this function is necessary for export of bulky cargoes. The discovery of TANGO1 and understanding its function has revealed that cargo export from the ER is not be vesicles but involves transient tunnels between the ER exit site and the next compartment of the secretory pathway. Biallelic Mutations in TANGO1 cause syndrome disease and complete loss of TANGO1 leads of defects in bone mineralization. These findings highlight the significance of TANGO1 in building and ER exit site, controlling the quantities and quality of cargo exported, which is necessary for life.
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