A metastasis suppressor is a protein that acts to slow or prevent

metastases 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, the ...

(secondary

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s) from spreading in the body of an organism with

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. 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.

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 Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

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 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, the ...

. 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. Metastasis suppressors were first identified using microcell-mediated chromosome transfer (MMCT), which introduces

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

s into intact recipient cells. Chromosomes 1, 6, 7, 8, 10, 11, 12, 16 and 17 harbor metastasis suppressor genes. 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 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture Cell culture or tissue culture is the process by which cells are ...

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.

Clinical applications

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

Prognosis

High NM23 expression is correlated with good prognosis in multiple tumor types, including breast cancer.

KAI1 CD82 (Cluster of Differentiation 82), or ''KAI1'', is a human protein encoded by the gene. This metastasis suppressor gene product is a membrane glycoprotein that is a member of the tetraspanin/transmembrane 4 superfamily. Expression of this ...

, 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.

Targets

Patients with NM23 -positive ovarian cancer respond better to

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...

than patients with NM23-negative tumors and esophageal squamous cell carcinoma. NM23 expression is correlated with increased survival after cisplatin treatment following surgery. 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.

Genes

Genes for about a dozen metastasis-suppressing proteins are known in humans and other animals, including

BRMS1 Breast cancer metastasis suppressor 1 is a protein that in humans is encoded by the ''BRMS1'' gene. This gene reduces the metastatic potential, but not the tumorogenicity, of human breast cancer and melanoma cell lines. The protein encoded by th ...

CRSP3 Mediator of RNA polymerase II transcription subunit 23 is an enzyme that in humans is encoded by the ''MED23'' gene. Function The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptio ...

, DRG1,

SDPR 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. This gene encodes a calcium-independent phospholipid-binding pro ...

KISS1 Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human met ...

NM23 Nucleoside diphosphate kinase A is an enzyme that in humans is encoded by the ''NME1'' gene. It is thought to be a metastasis suppressor. Function This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastat ...

and various TIMPs. Most act by altering aspects of signal transduction. *

is a suppressor active in

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, breast and

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowe ...

s and apparently inhibits the functioning of a kinase enzyme that promotes cell division. NM23 has eight family members. NM23-H1 and NM23-H2 suppress metastasis in multiple tumor types. NM23 expression can serve as a potential prognostic marker for survival in breast, ovarian, melanoma, gastric, hepatocellular and non-small cell carcinoma. It affects the MAPK and cytoskeleton-organizing cellular pathways, which contribute to its metastasis-suppressing functions. * MKK4 is a suppressor active in prostate and ovarian cancers It apparently functions by facilitating apoptosis, or death of abnormal cells such as cancer cells. *

is found in prostate and breast cancers. It forms complexes with proteins called

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...

s. Integrins link cells together. The complex formation may inhibit detachment and migration of cancer cells. *

promotes the activity of the

gap junction Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regula ...

s of cells. BRMS1 suppresses metastasis in multiple tumor types including ovarian, bladder, melanoma and non-small cell lung carcinoma. Clinically BRMS1 expression correlates with survival in breast cancer and non-small cell lung carcinoma. *

functions as a metastasis suppressor in breast cancer, potentially by priming cells to apoptosis. Cancer cells suppress the gene via promoter DNA methylation hence exemplifies the significance of epigenetic changes in cancer progression. *

is found in melanoma and breast cancers. It acts by synthesizing a protein receptor. * RHoGD12 is active in bladder cancer and inhibits proteins that aid in cancer cell migration. RhoGDI2 suppresses

endothelin 1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene ''EDN1'' is proteolytically processed to release endothelin 1. Endothe ...

(ET1), a vasoconstrictor correlated with higher clinical stage in bladder cancer. *

and VDUP1 are both active in melanoma. CRSP3 is a co-activator of genes involved in cancer growth, while VDUP1 inhibits a protein involved in cell proliferation. * Ectopic expression of Krüppel-like factor 17 ( KLF17) in highly metastatic 4T1 cells suppresses their metastatic potential without affecting primary tumor growth in a mouse model. KLF17 suppression promotes tumor cell epithelial-mesenchymal transition (EMT), which leads to metastasis. Transcription factor

Id1 DNA-binding protein inhibitor ID-1 is a protein that in humans is encoded by the ''ID1'' gene. Function The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with members of the basic HLH family of ...

is a direct target of KLF17 and mediates its metastatic functions. KLF17 expression is significantly downregulated and Id1 expression is upregulated in breast cancer metastasis. * GAS1 is found in melanoma. In poorly metastatic B16-F0 mouse melanoma cells, GAS1 knockdown promoted metastasis without affecting primary tumor growth. GAS1 suppresses metastasis by promoting apoptosis in disseminated cancer cells at secondary organs. Its expression is downregulated in metastatic clinical samples. * Primary tumor samples of colorectal cancer patients with liver metastasis showed gain of chromosomes 7p, 8q, 13q and 20q and loss of chromosomes 1p, 8p, 9p, 14q, 17p and 22q. Genes that are located in the regions of chromosomal loss include

MAP2K4 Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the ''MAP2K4'' gene. ''MAP2K4'' encodes a dual-specificity kinase that belongs to the Ser/Thr protein kinase family. MAP2K4 phosphorylates M ...

LLGL1 Lethal(2) giant larvae protein homolog 1 is a protein that in humans is encoded by the ''LLGL1'' gene. This gene encodes a protein that is similar to a tumor suppressor in Drosophila. The protein is part of a cytoskeletal network and is associ ...

FBLN1 FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein. Function Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin-co ...

, ELAC2, ALDH3A2,

ALDH3A1 Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ''ALDH3A1'' gene. Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-deriv ...

, SHMT1, ARSA, WNT7B, TNFRSF13B, UPK3A, TYMP, RASD1, PEMT and

TOP3A DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the ''TOP3A'' gene. Function This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes t ...

. These genes can potentially serve as metastasis suppressors. * In a basal-like primary breast cancer, mutations in

SNED1 SNED1 (Sushi, Nidogen, and EGF-like Domains) is an extracellular matrix (ECM) protein expressed at low levels in a wide range of tissues. The gene encodinSNED1is located in the human chromosome 2 at locus q37.3. The corresponding mRNA isolated from ...

and

FLNC The National Liberation Front of Corsica ( co, Fronte di liberazione naziunale di a Corsica or ; french: Front de libération nationale corse, abbreviated FLNC) was a militant group that advocates an independent state on the island of Corsica, ...

influenced metastasis.

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. These proteins are different from ones that act to suppress tumor growth.

References

External links

* {{Cite web , url= http://www.kurzweilai.net/super-natural-killer-cells-destroy-cancer-in-lymph-nodes-to-halt-metastasis , title= 'Super natural killer cells' destroy cancer in lymph nodes to halt metastasis , date= November 16, 2015 , website= Kurzweil Accelerating Intelligence , series= Newsletter , access-date= 2016-04-23 Antineoplastic drugs Proteins