Wednesday, June 27, 2012

Lynch Syndrome

Introduction


Lynch Syndrome is a genetic disease characterized by an increased risk of cancer of the lower digestive tract including the colon and rectum. Individuals who have Lynch syndrome are also predisposed to certain types of other cancers such as stomach, liver, pancreas, small intestine, urinary tract and brain. Women who have Lynch syndrome are at an increased risk of the ovaries and endometrium. Often referred to as hereditary nonpolyposis colorectal cancer (HNPCC), experts estimate that Lynch syndrome might be responsible for between two and seven percent of all colorectal cancers.

(Image from: Colon)


Lynch Syndrome often does not present with any clear symptoms until the individual is diagnosed with colorectal cancer at a young age (younger than 50 years old). Some individuals have a strong familial history of early onset colorectal cancers and might be directed by their primary care providers to a genetic counselor for confirmation of Lynch Syndrome. While literature previously indicated that those with Lynch Syndrome do not have colorectal polyps, more recent investigations indicate that not only do individuals with Lynch Syndrome have polyps; their polyps are more likely to develop into cancerous growths.

Knowing one's status regarding Lynch Syndrome and acting accordingly remains the leading method of prevention of colorectal cancer caused by heredity. Having Lynch Syndrome is not a confirmative diagnosis of cancer; it merely predisposes one to certain cancers, and early detection and removal of polyps is the best means of preventing a devastating cancer diagnosis.

Lynch Syndrome's Genetic Basis


Lynch Syndrome is a genetic condition that follows an autosomal dominant inheritance pattern, which means that only one of the affected individual's parents must pass the mutated allele on to the individual. While there are several potential gene mutations that indicate that the individual might have Lynch Syndrome, all the markers are mutations of the body's mismatch repair (MMR) genes. MMR genes protect the body from making mistakes in the DNA replication sequence.

In Lynch Syndrome, affected individuals have mutated MMR genes. The following four genes can be affected in individuals with Lynch Syndrome: MLH1, MSH2, MSH6 and PMS2. Genetic counseling can identify the MMR gene mutations, and while this will not prevent one from getting Lynch Syndrome, it can lead to early detection and life-saving excision of polyps or tumors.

The Role of MLH1


In particular, the expression of the MLH1 gene affects one's chances of developing cancers associated with Lynch Syndrome because of the unique role MLH1 plays in the process of DNA replication at the cellular level. When DNA replicates, the process ideally creates identical copies of itself. Sometimes, however, the DNA polymerase makes mistakes in the process that results in a mutated gene or genes in the DNA strand. DNA polymerase is responsible for arranging the base pairs at the replication fork of a DNA molecule. Typically these mistakes involve arranging bases in non-complementary pairings.

When DNA polymerase makes mistakes, the body's MLH1 genes are responsible for the repair of such mistakes. MLH1 in combination with other genes, codes for certain protein complexes that control the body's response to the mismatched base pairings. MLH1, therefore, is responsible for recognizing the mistakes that have been made in the replicated strand. This mismatch can be corrected by excising the incorrect part and replacing it with the correct part. MMR genes perform this task quickly, so that the mutated genes do not become expressed in the replicated cells.

When MLH1 becomes mutated, as can be seen in Lynch Syndrome, the body cannot recognize nor repair the damage to the mismatched base pairings quickly enough before cellular replication occurs. The cells with mutated DNA continue to grow and replicate themselves, mutations intact. This can lead to the proliferation of cells that contain irreversibly mutated DNA, which can lead to malignant tumors in the affected areas of the body.

Fortunately, genetic screenings can test individuals for the presence of the MMR gene mutations. Knowing that one has the genetic mutation, and knowing more specifically which gene is mutated, can greatly improve the prognosis for individuals with Lynch Syndrome. Armed with the knowledge that Lynch Syndrome is hereditary can also improve care provided to any offspring or family members who might also have Lynch Syndrome.

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Sunday, June 24, 2012

Hereditary Breast and Ovarian Cancer

Breast and ovarian cancers are among the most common cancers for women. Indeed, more than 12% of women will be affected by breast cancer during their lifespan. Breast cancer can be an invasive cancer; ovarian cancer has one of the highest mortality rates. Both breast cancer and ovarian cancer can occur more frequently in individuals who have an inherited genetic mutation. If an individual has a mutation in his or her BRCA1 or BRCA2 gene, her chance of getting breast cancer increases to 60%. This astonishing five-fold increase is due to the way the mutation changes the body’s responses.


(Image from: The roles of BRCA1 and BRCA2 in DNA repair )



Mutated BRCA1 and BRCA2 do not only affect the breast, nor does BRCA1 or BRCA2 only affect women. Men who have BRCA2 are considerably more likely to develop male breast cancer, pancreatic cancer and prostate cancer at an early age. Indeed, families who have the BRCA1 or BRCA2 mutation have a much greater risk of many types of cancer including uterine, cervical, pancreatic, testicular and other cancers.

Breast and ovarian cancers devastate families and are the subjects of worldwide research studies to determine the link between the BRCA1/BRCA2 mutation and the incidence of early-onset cancers. Studies have found that breast and ovarian cancer as a result of BRCA1 or BRCA2 mutations occur most common in families who have a history of many incidences of breast and ovarian cancer, or in families who have a history of cancer that appears in more than just one site in the body. BRCA1 and BRCA2 mutations also occur more frequently in families from a Central/ Eastern European Jewish background.

With treatment, breast and ovarian cancers can be treatable. While tests to determine whether or not one has the BRCA1/BRCA2 gene mutation are costly, the information they yield can be invaluable to the individual. With proper preventative screenings and tests, one can help identify potentially deadly cancers early enough for intervention.

Function of the BRCA1 Gene


Located on chromosome 17, BRCA1 serves a vital purpose in the body: it suppresses tumor growth by providing the code for a protein that repairs DNA. DNA is arranged in a tight double-helix formation that uses supportive bridges to maintain its shape. When these bridges are removed as happens during replication, the DNA strand can become damaged and requires repair. Other means by which DNA may become damaged includes exposures to environmental toxins and radiation. Damaged DNA causes cells to improperly use their safeguards, and as a result, the cellular differentiation can proliferate out of control, creating tumors.

Healthy BRCA1 works to curb this wild growth because it mends the damage in DNA double helices. In the nucleus of the cell, BRCA1 works with other proteins such as those created by the genes RAD51 and BARD1 to determine the types of breaks and then repair them. Damaged DNA sometimes becomes damaged when DNA is damaged, it responds with the potential for hypertrophy in cells and tissues. This uncontrolled growth creates tumors, and in some cases malignancies. BRCA1’s protein, therefore, protects the integrity of the cell’s blueprint by repairing damage to the structure of the DNA. When BRCA1 becomes mutated, DNA can no longer be repaired, resulting in cancerous growths.
When an individual has a mutated BRCA1, its structural differences create limitations in the gene’s functional ability to create the protein that helps to repair the DNA damage. This leaves the cell prone to dysplasia and hyperplasia, which can eventually lead to tumor growth and a diagnosis of cancer in the affected area of the body. With BRCA1, the tumors are typically associated with the breasts and ovaries.

Mutations in Other Genes


In addition to BRCA1 and BRCA2, mutations in other genes may play a part in inherited predispositions to breast and ovarian cancers. These genes include CHD1, TP53, PTEN, STK11 and others. While these genes might also play an important role in the tendency toward breast cancer, the vast majority of hereditary breast cancers can be traced to a mutation in BRCA1 or BRCA2. These deadly mutations can be identified in 10 to 15 percent of all diagnoses of ovarian cancer and in 5 to 10 percent of all diagnoses of breast cancer. Because of the invasive and potentially fatal effects of mutations in BRCA1 and BRCA2, scientists center their studies on BRCA1 and BRCA2.


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Wednesday, June 20, 2012

Hypoxia


(Image from: Hypoxia)



Hypoxia is a pathological condition in which either the whole body (generalized hypoxia) or a region of the body (tissue hypoxia ) is deprived of oxygen. Tissue hypoxia commonly occurs in cancerous tumors when rapid growth causes the tumor to outgrow its blood supply resulting in regions with significantly lower oxygen concentrations. It is a negative prognostic and predictive factor, as it contributes to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, altered metabolism and genomic instability.


The effects of tissue hypoxia are mediated through the HIF (hypoxia inducible factor) signaling cascade. Under normoxic conditions, the alpha subunits of HIF are hydroxylated by HIF prolyl-hydroxylases, which leads to ubiquitination by the VHL E3 ubiquitin ligase and subsequent degradation of HIF by proteasomes. Under hypoxic conditions, a buildup of succinate combined with a lack of oxygen results in the inhibition of HIF prolyl-hydroxylase. HIF subsequently accumulates and translocates to the nucleus where it dimerizes with the beta isoform of HIF. This dimer interacts with cofactors such as ARNT, CBP/p300 and the Pol II complex to activate the HRE (hypoxic response element), which initiates the transcription of various genes including VEGFA, Glut1 and CA9.


Hypoxia in tumors is closely associated with tumor aggressiveness and resistance to radio- and chemotherapeutic treatment. Therefore, reliable markers for hypoxia represent both valuable diagnostic markers and potential targets for investigation. CAIX (carbonic anhydrase IX) has recently been identified as a hypoxia and tumor biomarker. CAIX is a transmembrane protein that belongs to the 15 member carbonic anhydrase enzyme family and is involved in regulating cellular pH. CAIX expression is restricted to very few normal tissues, in particular the membranes of gastric mucosal epithelial cells. Under hypoxic conditions, the transcription factor HIF-1 transactivates the CA9 gene, resulting in expression of the CAIX protein in the hypoxic cells. Due to its stability, cell surface transmembrane localization and rapid increase in protein level in response to HIF-1 alpha accumulation, CAIX is an excellent biomarker of hypoxic regions in many solid tumors. CAIX has been considered one of the best cellular biomarkers of hypoxia, and recent studies have suggested that CAIX expression may be a valuable prognostic indicator for overall survival.


Tumor hypoxia has recently been proposed as a target for cancer therapy. The strategies for this type of therapy include developing drugs that are activated under hypoxic conditions and taking advantage of the selective induction of HIF under hypoxic conditions to develop gene therapies. Treatments that can exploit the unique features of hypoxic tumors may one day change this negative prognostic indicator into one that is advantageous for targeted treatments.


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Monday, June 18, 2012

Hepatic Adenoma

Hepatic adenoma, sometimes referred to as heptatocellular adenoma, is non-cancerous liver tumors. Hepatic adenoma occurs most frequently in young women and is related to the prolonged use of oral contraceptives. While the notion of tumors or lesions in the liver seems to be cause for immediate alarm, doctors discover many of these tumors during ultrasound scans for other reasons. Emergency rooms also discover the presence of hepatic adenoma in individuals who present at the emergency room for severe abdominal pain and internal bleeding from the ruptured adenoma.

Hepatic adenoma that does not cause physical symptoms, referred to as asymptomatic hepatic adenoma, require little more than watchful waiting and diagnostic testing such as imaging studies to rule out the progression of the adenoma. These imaging studies will monitor any growth or changes of the adenoma to rule out its progression. If the hepatic adenoma has ruptured and is causing liver bleeding, then a surgeon might excise the tumor from the liver to prevent further problems.

While a hepatic adenoma does not cause disease, physicians recognize that there is some risk of benign adenoma undergoing changes that might result in a malignancy in the liver. These malignancies, called hepatocellular carcinoma (HCC), are a deadly form of cancer that can necessitate extreme medical measures to prevent the spread of disease. Not all hepatic adenoma will undergo this transformation, however, and physicians feel it would be inappropriate to treat all adenoma patients with an aggressive hand. To identify which hepatic adenoma may transform into HCC, doctors now use an innovative genetic grading system to determine risk.


(Image from: Pathogenesis of human hepatocellular carcinoma)


Genetic Basis of Hepatic Adenoma


Doctors use genetic testing to determine the risk of hepatic adenoma transforming into HCC in one of two ways. First, the adenoma is genetically tested to see if it cells’ nuclei have a certain protein in them that causes other types of liver cancers: HCC and hepatoblastoma. The beta-catenin gene, also called CTNNB1, makes the protein called beta-catenin, which is an important part of normal body function. Inside some hepatic adenoma, however, beta-catenin can move into the nucleus of the cells and cause excessive DNA replication to occur leading to abnormal growth and potentially HCC. The presence of beta-catenin in the hepatic adenoma’s nucleus indicates that it may be shifting into a malignancy.

The second approach to genetic testing as a means to determine whether or not hepatic adenoma is likely to transform is to test the entire individual’s genome for any mutated genes. Specifically, individuals whose genome contains a mutation at the hepatocyte nuclear factor-1a gene (HNF1a) and/or the TCF1 gene can sometimes have transformation of the benign adenoma into carcinoma. These genes are responsible for how liver cells divide. If they are mutated, liver cancer can result. Up to 50% of individuals with a mutated TCF1 gene have hepatic adenoma that will undergo transformation into hepatocellular carcinoma.


Using Genetic Screening to Diagnose


With the advent of new genetic testing for individuals with hepatic adenoma, doctors are able to more readily predict if a patient’s benign adenoma is likely to develop into HCC. This allows the physician to tailor his or her approach with delicacy and only pursue aggressive treatment for those individuals likely to have their adenoma progress into HCC. Genetic testing for individuals with hepatic adenoma is a remarkable new approach to identification and treatment and has the potential to save many lives. As genetic testing becomes more commonplace, barriers to providing this testing will be reduced and more physicians will likely use this technology to help their patients better understand their course of disease.


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Wednesday, June 13, 2012

Smooth Muscle

● What is smooth muscle?

Smooth muscle is muscle that is involuntary and that is not striated. There are two subgroups of smooth muscle: single unit, and multi unit. Single unit smooth muscle, which is also known as unitary smooth muscle, is innervated at the single cell level by the autonomic nervous system. The single cells are located within bundles or sheets of muscle tissue.

The action potential from the nervous system moves to accompanying cells through gap junctions in a way that leads to the contraction of the entire sheet or bundle. This whole sheet contraction is known as a syncytium, which is a cytoplasm mass with many nuclei that does not have separation into individual cells.

Smooth muscle tissues in the multi unit groupings also have nerve penetrations at the individual cell level. As a result, gradual responses can occur, including those responsible for fine motor control, similar to the way motor units control fine movements through skeletal muscles.

Smooth muscle is located in a variety of regions within the human body, including inside the blood vessel walls, where it is known as vascular smooth muscle. It is also found in the tunica media part of small and large arteries, veins, and arterioles.

Smooth muscle is also located in the urinary bladder, the lymphatic vessels, the uterus, where it is known as uterine smooth muscle, the respiratory and gastrointestinal tracts, the female and male reproductive tracts, the iris of the eye, and the ciliary muscle.

Smooth muscle cells are essentially structured and work the same way regardless of which organs they inhabit, but the stimuli required to trigger them vary considerably, which is why they can perform unique actions within the body at different times. The kidney glomeruli also host cells that resemble smooth muscle cells; these are known as mesangial cells.



(Image from: Actin myosin filaments)


● What is the molecular structure of smooth muscle tissue?

Much of what makes up smooth muscle cell cytoplasm is composed of actin and myosin molecules. Together, actin and myosin can contract. There are several tensile structures linked in a chain that allow the full smooth muscle tissue to contract with myosin and actin.


● An introduction to smooth muscle myosin

Myosin is predominantly composed of class ii when found in smooth muscle. Class ii myosin involves a pair of heavy chains that make up the head and tail areas. The heavy chains include N terminal head domains and C terminals are arranged in coiled coils that keep the two heavy chains linked. As a result, two heads are present in myosin ii.

There are also 4 light chains in myosin ii, with 2 chains in each head. These light chains keep the heavy chains together between the tail and the head. Hundreds of kinds of myosin structures can be made from different light and heavy chain combinations.


● An introduction to smooth muscle actin

The contractile machinery is made up of thin filaments that are primarily made from a and y actin. Alpha actin, or a actin in smooth muscle, is the isoform of smooth muscle that is most common. B actin is also quite prevalent, but it does not affect muscle contraction. B actin forms a polymer beneath the plasma membrane when a contracting stimulant is present, which means it might help in generating or sustaining mechanical tension.

Alpha actin also has unique isoforms at a genetic level, which means that there are specific isoforms in skeletal muscle, smooth muscle, and cardiac muscle with alpha actin. There is between 2 and 10 times as much myosin as actin in smooth muscle, while the ratio of myosin to actin is 6 to 1 in skeletal muscle and 4 to 1 in muscles within the heart.


● What is a smooth muscle actin antibody?

A smooth muscle actin antibody helps tag myoepithelial cells, myofibroblasts, and ordinary smooth muscle cells. The actin antibody can prove helpful for helping physicians identify a variety of muscular cancers and neoplasms, including pleomorphic adenomas, leiomyosarcomas, and leiomyomas.

The antibody is sensitive to the alpha actin form of smooth muscles. The antibody tends to specifically react with this actin when immunoblotting assays are performed. The antibody helps label the cells in smooth muscle in tissue sections that are embedded in paraffin, fixed in formalin, or frozen.


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Sunday, June 10, 2012

Genetic and Biochemical Markers in Detection of Cancer

Cancer may be defined as the unregulated proliferation of abnormal cells of a particular type. Cancer cells are said to be of a particular “cell line” and a group of such cells represents a tumor. The original site of the tumor is known as the primary site or, simply, “the primary”. Some of these abnormal cells will eventually detach from their original site and are carried to other areas of the body where they establish themselves by forming a new blood supply (angiogenesis) and continue to replicate themselves. This breaking away and re-establishment at a different location is called metastasis, and these growths are called metastatic, or secondary tumors.


(Image from: Models of the metastatic process)


Physicians have long been aware that the presence and number of metastases is a direct predictor or both short and long term mortality in cancer patients. Since the presence or absence of metastasis is thus the most important factor in predicting the “treatability” of any form of cancer, it is of great importance that cancer be diagnosed before metastasis has occurred. The early diagnosis of cancer, which is to say prior to metastasis, is desirable for three reasons:

1. To increase the probability of diagnosis prior to spread.

When cancer is detected prior to the development of metastasis, surgical removal or other such direct procedures as cryotherapy will result in a “cure rate” of 100%. However, the detection of metastatic disease by visual inspection alone is known to be inadequate. This fact has led to intensive research in the use of “markers,” such as genetic analysis and biochemical testing, to detect both metastasis and the potential of primary tumors to produce metastatic lesions.


2. To decrease the amount of therapy required, and

The number of cancerous cells present is called the “tumor load.” Obviously, the greater the tumor load, a greater the amount of a particular therapeutic agent (e.g. chemotherapy or radiation therapy) will be required to destroy the cancer cells. Unfortunately, all such anti-cancer therapies will have the potential to affect other, healthy cells as well. Since these undesirable effects are usually “dose-dependent,” it is desirable to administer the minimum amount of a particular agent that is sufficient to destroy the cancer cells yet minimize damage to healthy non-cancerous cells.


3. To decrease the likelihood that therapy-resistant cell lines will develop.

Everyone is probably familiar with the fact that bacteria and other pathogens have a propensity to develop a resistance, or decreased susceptibility, to a number of antibiotics. In a similar vein, tumor cells that are less sensitive to chemotherapeutic drugs will live slightly longer than their more-susceptible counterparts. When these less-sensitive cells divide, their “daughter” cells will inherit that resistance and, over time, a new therapy-resistant cell line will emerge. These new cell lines are a major factor in the failure of many anti-cancer regimens.


As noted previously, there is a great deal of interest regarding the use of genetic and biochemical markers in the early detection of both primary tumors and metastatic disease. The most familiar genetic marker currently in clinical use are related to breast cancer and mutations of the BRCA1 and BRCA2 genes, while the more familiar biochemical markers of cancer are the Prostate-Specific Antigen (PSA) in prostate cancer and the Carcinoembryonic antigen (CEA) , which may be detected in the blood of those with colorectal cancer.

The BRCA1 genes and BRCA2 genes provide the genetic code that produces certain proteins that either repair or destroy defective DNA during cell division. Clinically-detectable mutations in these genes are known to carry an increased risk of breast cancer and the amount of their associated proteins present in the bloodstream are under active investigation in the potential detection and therapeutic management of that condition.

At this time, the use of biochemical markers in cancer is hampered by issues of non-specificity and non-sensitivity. As an example, the Prostate-Specific Antigen is elevated in prostate cancer. However, it is also elevated in both acute and prostatitis as well, making it a poor indicator of the presence or absence of prostate cancer. By the same token, the absence of an elevated blood level of the Carcinoembryonic antigen does not preclude the presence of colon cancer and this marker may be elevated in cases of colitis and thus yield a false-positive result when used as a cancer screening examination.

In conclusion, this brief essay has reviewed the importance of early detection of both cancer and its metastatic component. Although at this time the use of genetic and biochemical markers in diagnostic and therapeutic strategies is still evolving, these areas exhibit considerable potential for future refinement.

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Wednesday, June 6, 2012

Proto-Oncogenes

● What are Proto-Oncogenes

Proto-oncogenes are a subgroup of genes that, when mutated, are directly involved in the development of cancer. The mutation of proto-oncogenes causes normal cells to mutate into cancerous cells. A mutation of a proto-oncogene is a dominant type of mutation, and once the proto-oncogene becomes mutated it is classified as an oncogene. Before a proto-oncogene becomes affected it is often responsible for encoding protein function related to cell division as well as inhibition of cell differentiation and cellular apoptosis. These are functions that are pivotal for normal physiologic function and the mutation feeds off of this relationship. When the oncogene takes over, it typically ramps up these functions and thus increases the overall rate of cancer cell development without an inhibitory control present to halt the production of the cancerous cells. Given this fact, oncogenes are the main target in anti-cancer drug design.


● Transformation From Proto-Oncogenes to Oncogenes

As it is known today, there are over 40 different proto-oncogenes within the human genome. The transformation from a proto-oncogene to an oncogene is a very specific mutation. Oncogenes are a byproduct of mutations that increase the expression level of a proto-oncogene because these are the type of mutations that are going to lead to the greatest form of cancer cell proliferation. There are a number of genetic mechanisms that are correlated with proto-oncogene mutations,
such as:

  1. Point mutation, deletion, or insertion resulting in hyperactive gene product.
  2. Point mutation, deletion, or insertion within a promoter region of proto-oncogene that regulates transcription.
  3. Gene amplification leading to extra chromosomal copies of the mutated gene.
  4. Translocation events that move the proto-oncogene to a new locus leading to higher expression.
  5. Chromosomal translocations leading to proto-oncogene fusion and a secondary gene, resulting in a fusion protein with oncogenic activity.


(Image from: Cancer Genetics - Oncogenes)



● Oncogenic Examples

One place where proto-oncogenes have a large role is the coding of cell surface receptors, which act as a communication conduit between the extracellular environment and the intracellular environment. These receptors are composed of three separate parts that function simultaneously in order to provide optimal signaling. The extracellular region is similar to an antenna in that it collects an outside signal from the environment. The transmembrane region spans the length of the plasma membrane. The intracellular region possesses its own enzymatic activity and interacts with other proteins found within the cell.
A cell responds to signals outside from the extracellular environment in order to participate in proper growth and division. This occurs through ligand binding to the extracellular component of the transmembrane receptors. Ligands often take the form of growth factors to stimulate growth or angiogenic factors, which stimulate vascularization. Comformational changes occur with the binding of the ligand, which leads to the activation of intracellular domain resulting in a cascade effect affecting cell growth, proliferation, vascularization, or apoptosis. A specific example of this includes epidermal growth factor and epidermal growth factor receptor, which are responsible for growth factor mediation.

Proto-oncogenes are also responsible for coding proteins that may have a downstream effect resulting in stimulation of cell growth and division. A specific example of this is the RAS gene family, HRAS and KRAS. Along the same lines, there are some proto-oncogenes that are responsible for continuing cells through the cell cycle when specific signals are received by receptors. When these proto-oncogenes are overly expressed or expression is turned on at the wrong time, cancer cells begin to appear.

Oncogenes can also be expressed through translocation events occurring at the chromosome level. The best example of this is the Philadelphia chromosome. In this example, a crossover event occurs between chromosome 9 and chromosome 22. This results in interaction between the BCR gene found on chromosome 22 with the ABL1 gene found on chromosome 9. The fusion of these genes results in the production of the protein with high protein tyrosine kinase activity. If this expression goes about unregulated, there are a number of other proteins involved in cell cycle regulation that are activated to stimulate cell division. This is the gene that is often associated with numerous forms of leukemia.

Proto-oncogenes are important to understand in the development and treatment of cancer and through further research, cancer treatment can continue to progress.


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Sunday, June 3, 2012

E-cadherin is a classic cadherin that acts as an adhesion molecule and a cellular regulator



E-cadherin (epithelial cadherin) is a member of the cadherin superfamily of proteins, a group of 80 glycoproteins that are broadly involved in cell to cell adhesion via calcium-mediated homotypic interactions. It is considered to be a tumor suppressor gene because its interactions strongly bind cells together, limiting migration. E-cadherin is a type I "classic cadherin" along with neural (N) and placental (P) cadherins and is coded by the CDH1 gene. All classic cadherins contain a highly conserved transmembrane domain with a cytoplasmic tail that binds to the actin cytoskeleton via an alpha- and beta- catenin "bridge" that binds to the C-terminus. Type I and II cadherins contain an extracellular domain consisting of five identical 110 amino acid repeats, which form the basis for their role as adhesion molecules.

E-cadherin is important during early development, expressing throughout the cells soon after the first mitotic division and initiating compaction by the 8-cell stage. Soon afterwards, its expression is restricted to areas in contact with neighboring cells. In addition to its role as an adhesion molecule, E-cadherin has broad signaling properties that influence the fate of cells, especially during early differentiation. When E-cadherin is disrupted, embryonic cells lose their pluripotency and prematurely differentiate. The pattern of E-cadherin expression can be assessed via either a transgenic fluorophore tag (primarily for in vivo work) or an E-cadherin antibody for immunohistochemistry. An analysis of this expression indicates that E-cadherin is important in the establishment of left-right symmetry during morphogenesis.

The viral-mediated overexpression of E-cadherin has been used to "reprogram" embryonic cells, whereas its deletion inhibits reprogramming. Interestingly, E-cadherin is often downregulated in many cancers. It is unknown whether this has any influence over the undifferentiation often seen in metastatic tumors.

After embryonic differentiation, E-cadherin is seen largely in the epithelial cells of the gut and lungs but is also present in the kidney, skin, and liver to some extent. In these tissues, cadherin is responsible for binding cells together, often forming "belt desmosomes", which circumscribe the cell's soma. This allows the cell to both maintain its position relative to neighboring cells and, by forming a cellular seal across the entire epithelial layer, carefully control the transport of nutrient and waste particles across the membrane.

When binding to beta-catenin is disrupted (such as via dephosphorylation at the beta-catenin binding site), the E-cadherin molecule is no longer anchored to the cytoskeleton. This results in destabilization and rapid turnover, decreasing the number of cadherin-cadherin interactions at the intercellular junction, consequently reducing its strength and integrity. Similarly, the prevention of calcium binding at the extracellular domain results in a conformational change that disrupts E-cadherin's homotypic interactions.

The assessment of E-cadherin is often of clinical significance, as it is dysregulated in several forms of cancer. A good E-cadherin antibody can be used to visualize the level and pattern of protein expression via immunofluorescence or similar techniques. During metastasis, many cancers of the breast, skin, and gut substantially downregulate their E-cadherin expression. The effects of this downregulation are twofold: first, the cell to cell adhesion of the tumor cells is reduced, which lets the cancer cells spread and metastasize distant tissues; furthermore, the loosened cancer cells create holes in the basement membrane, which allows the egress of tumor cells from the lumen.


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