IPS Cell Therapy IPS Cell Therapy – genetherapy.me

By LizaAVILA

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Stem Cell Research is an amazing field right now, and promises to be a powerful and potent tool to help us live longer and healthier lives. Just last month, for example, Stem Cell Therapy was used to restore sight in patients with severe retinal deterioration, allowing them to see clearer than they had in years, or even decades.

Now, there is another form of Stem Cell Treatment on the horizonthis one of a very different form. Stem Cells have now been used as a mechanism to deliver medical treatment designed to eliminate cancer cells, even in hard to reach places. One issue with current cancer treatments is that, treatments that are effective at treating tumors on the surface of the brain cannot be performed safely when the tumor is deeper within the brains tissues.

Stem Cells have the fantastic ability to transform into any other kind of cell within the human body, given the appropriate stimulation. As of today, most of these cells come from Embryonic Lines, but researchers are learning how to backwards engineer cells in the human body, reverting them back to their embryonic state. These cells are known as Induced Pluripotent Stem Cells.

How Does This Stem Cell Cancer Treatment Work?

Using genetic engineering, it is possible to create stem cells that are designed to release a chemical known as Pseudomonas Exotoxin, which has the ability to destroy certain tumor cells in the human brain.

What is Pseudomonas Exotoxin?

Pseudomonas Exotoxin is a compound that is naturally released by a form of bacteria known as Pseudomonas Aeruginosa. This chemical is toxic to brain tumor cells because it prevents polypeptides from growing longer, essentially preventing the polypeptides from growing and reproducing. When used in a specific manner, this toxin has the ability to destroy cancerous and malignant tissue without negatively impacting healthy tissue. In addition to its potential as a cancer treatment, there is also evidence that the therapy could be used for the treatment of Hepatitis B.

PE and Similar Toxins Have been Used Therapeutically in the Past

As of now, this chemical, which we will refer to for the rest of the article as PE, has been used as a cancer treatment before, but there are major limitations regarding the use of PE for particular cancers, not because of the risks of the treatment, but because of the lack of an effective method to deliver the medication to where it is needed.

For example, similar chemicals have been highly effective in the treatment of a large number of blood cancers, but havent been nearly as effective in larger, more inaccessible tumors. The chemicals break down or become metabolized before they can fully do their job.

How do Stem Cells Increase the Effectiveness of PE Cancer Treatment

Right now, PE has to be created in a laboratory before it is administered, which is not very effective for these embedded cancers. By using Stem Cells as an intermediary, it is possible to deliver the medication to deeper areas of the brain more effectively, theoretically highly increasing the efficacy of the treatment.

The leader of this Stem Cell Research is Harvard researcher Dr. Khalis Shah. His goal was to find an effective means to treat these deep brain tumors which are not easily treated by methods available today. In utilizing Stem Cells, Dr. Shah has potentially found a means by which the stem cells can constantly deliver this Cancer Toxin to the tumor area. The cells remain active and are fed by the body, which allows them to provide a steady stream of treatment that is impossible to provide via any other known method.

This research is still in its early stages, and has not yet reached human trials, but in mice, the PE Toxin worked exactly as hypothesized and was able to starve out tumors by preventing them from replicating effectively.

Perhaps this might seem a bit less complicated than it actually is. One of the major hurdles that had to be overcome was that this Toxin would normally be strong enough to kill the cell that hosted it. In order for the Stem Cells to release the cancer, they had to be able to withstand the effects of PE, themselves. Using genetic engineering, Dr. Shah and his associates were able to create a cell that is capable of both producing and withstanding the effects of the toxin.

Stem Cell delivered medical therapy is a 21st century form of medical treatment that researchers are just beginning to learn how to effectively utilize. Essentially, this treatment takes a stem cell and converts it into a unique symbiotic tool capable of feeding off of the host for energy in order to perform a potentially life-saving function. Its really quite fascinating.

How Does PE Not Damage or Kill Brain Cells Indiscriminately?

You might be concerned about the idea of a patient having a toxin injected into the brain to cure a disease. It sounds almost like a dangerous, tribal, homeopathic remedy. In reality, the researchers have been able to harness the destructive power of the toxin and re-engineer it so that it directly targets cancer cells while having limited negative effects on healthy, non-cancerous tissue.

The toxin does its damage after it has been absorbed by a cell. By retooling the toxin so that it does not readily absorb into healthy cells, the dangers associated with having such a potentially dangerous toxin in the brain are seriously and significantly mitigated.

Beyond that, Dr. Shah and his associates have been able to take steps to effectively turn off PE while it is inside the host stem cell, and only activates when it has entered the cancerous tissue. Dr. Shah explains that, although this research has only been conducted in animal subjects, there is no known reason why the effectiveness and safety of the treatment would not be applicable to human patients.

In this treatment, surgeons remove as much of the tumor as possible from the brain, and insert the engineered Stem Cells submerged in a sterile gel in the area where the tumor was removed or partially still exists. Researchers found that, when they used this treatment on laboratory rats, they could tell through imaging and analysis that the modified PE toxin effectively killed the cancer cells, and that this cancer treatment effectively lengthened the life of the rat, as compared to control subjects.

Whats the Next Step?

Of course, cancer treatment is far more complex than a single treatment, no matter how effective that treatment may be. Because human cancer treatment is a comprehensive therapy approach, the end goal of this research is to create a form of therapy in which the method used in animal subjects is combined with other existing approaches, increasing and maximizing the effectiveness of the comprehensive treatment.

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A recent change in how well we understand stem cells may make it easier for scientists and researchers to gather stem cells for use in scientific research as well as medical application. A new study was released in the research publication, Cell, which was performed by representatives from the University of California San Francisco.

One of the issues which hinder the use of stem cells as a more widespread treatment or field of research is that researchers and patients have a bottleneck of available healthy stem cell lines which can be used for research. Researchers hope that this new discovery will allow future scientific discoveries and applications in the areas of creating new and healthy tissue for patients with kidney failure or any other form of organ tissue failure. The future of medical therapy lies with Stem Cell Research, but many other forms of treatment, including Hormone Replacement Therapy, are already in practice today.

Researchers have discovered that it is possible to essentially flip a switch in an adult cell, reverting it back to the preliminary state at which cells existed in one of the earliest stages of developmentthe embryonic stem cell. Medical researchers hypothesize that Stem Cell treatments could be used for a variety of medical health issues which plague the world today, including kidney failure, liver disease, and Type-1 and Type-2 Diabetes.

Use of Embryonic Stem Cells Contentious

There is an ethical issue in Stem Cell Research today. Many Pro-Life Advocates are vociferously against the use of Embryonic Stem Cells harvested from procedures such as fertility treatments designed for conception. They believe that the use of embryonic stem cells harvested from donors and couples looking to conceive is unethical.

Using current research, it may be possible to bypass this ethical quandary completely by using adult cells and converting them into embryonic stem cells. Furthermore, because these stem cells are genetic derivatives of the patient from which the adult cells were harvested, this potentially paves the way for patient-specific medical treatments using stem cells.

After adult cells have been converted back into Embryonic Stem Cells, it will be possible to convert them into any possible cell that the patient needs or would benefit from.

Hijacking the Blueprint of the Cell Allows Scientists to Revert Adult Cells to their Earliest State

Researchers have increased the capacity to produce Embryonic Stem Cells by identifying previously unrecognized biochemical processes which tell human cells how to develop. In essence, researchers have discovered how the body blueprints cells, and can change the blueprints so that a new cell is made.

By utilizing these newly recognized pathways, it is possible to create new stem cells more quickly than ever before. One of the researchers explains the implications of this research. Dr. Miguel Ramalho-Santos is an associate professor of obstetrics, medicine, and cancer research at the University of California San Francisco. Dr. Ramalho-Santos is also a member of the Broad Center of Regenerative Medicine and Stem Cell Research.

He explains that these stem cell discoveries have the ability to alter the way that the medical sciences can take advantage of stem cells with regard to both cancer research and regenerative medicine. Dr. Ramalho-Santos was the lead researcher for this study, and the research was largely funded by the Director of the National Institutes of Health New Innovator Award, granted to promising young researchers which are leading highly innovative and promising medical research studies.

Dr. Ramalho-Santos research builds off of earlier research which discovered that it was possible to take adult cells and turn them back into embryonic stem cells. These stem cells dont have any inherent aging processes, and they can be turned into any other kind of tissue. In the process of this conversion, the adult cells lose all of their unique characteristics, leaving them in an ultimately immature and malleable state.

This earlier research was conducted by researchers from UC San Francisco in partnership with Dr. Shinya Yamanaka from Kyoto University and Gladstone Institutes. These entities all gained a piece of the Nobel Prize in Physiology or Medicine from their part in the study.

Pluripotent Stem Cells vs. Embryonic Stem Cells

Thus far, weve described these cells as Embryonic Stem Cells, but in fact, the more accurate term for these cells are Induced Pluripotent Stem Cells (IPS). These cells are biologically and functionally similar to Embryonic Stem Cells, but have a different name because they are sourced from adult cells. The difference between Induced Pluripotent Stem Cells and Embryonic Stem Cells is that Induced Pluripotent Stem Cells do seem to retain some of the characteristics of their previous state, which appears to limit their ability to convert into any other type of cell. This new research identifies new pathways by which it may be possible to increase the number of cells that an individual IPS Cell can turn into, perhaps allowing them to convert into any other kind of human cell.

Induced Pluripotent Stem Cells are not explicitly considered an alternative to Embryonic Stem Cells, but are considered a different approach to produce similar cells. If researchers fully uncover the mechanisms of how to reprogram these cells, it will lower many barriers to stem cell research and the availability of stem cell treatments.

As of today, researchers have figured out how to make these Induced Pluripotent Stem Cells, but the percentage of adult cells which are reverted successfully is quite low, and frequently, these cells still show some aspects of specialization, which limits their use.

How Do Scientists Make Stem Cells From Adult Cells?

There are genes within every cell which have the ability to induce pluripotency, reverting the cell to an earlier stage of specialization. The initial stage of this process is the result of activating Yamanaka Factors, specific genes that initiate this reversion process.

As of today, this process of de-maturation is not completely understood, and researchers realized from the start that the cells they created were not truly identical to Embryonic Stem Cells, because they still showed signs of their former lives, which often prevented them from being successfully reprogrammed.

The new research conducted by Dr. Ramalho-Santos appears to increase our knowledge regarding how these cells work, and how to program them more effectively. Dr. Ramalho-Santos and his team discovered more genes associated with these programming/reprogramming processes, and by manipulating them, they have increased the viability and range of particular stem cells.

It appears that these genetic impulses are constantly at play to maintain the structure and function of a cell, and that by systematically removing these safeguards, it is possible to increase the ability to alter these cells.

This research increases researchers ability to produce these stem cells, by increasing the ability of medical scientists to produce adequate numbers of stem cells, while also increasing the range of potential treatment options by more effectively inducing the total pluripotency which is available in Embryonic Stem Cells. This research may also help scientists treat certain forms of cancer which are the result of malfunctions of these genes.

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocytic cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular cellular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim (see Figure 3) or can appear somewhat eczematous. They often ulcerate (see Figure 3). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCIs website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

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Figure 2. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

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Figure 3. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

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Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

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Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer. With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a persons skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowlers solution and Bells asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenatetreated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

However, the effect of arsenic on skin cancer risk may be more complex than previously thought. Evidence from in vivo models indicate that arsenic, alone or in combination with itraconazole, can inhibit the hedgehog pathway in cells with wild-type or mutated Smoothened by binding to GLI2 proteins; in this way, these drugs demonstrated inhibition of BCC growth in these animal models.[26,27] Additionally, the effect of arsenic on skin cancer risk may be modified by certain variants in nucleotide excision repair genes (xeroderma pigmentosum [XP] types A and D).[28]

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[29] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[30]

Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[31-33] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[34,35] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[31,36] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[37] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[38-43] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[44-47] however, other studies have contradicted this finding.[48-51] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[52] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[53,54] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[55,56] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[57] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[58] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[59]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[60,61] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[62] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[60,63]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[64] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[59,65] The clinical features of BCNS differ more among families than within families.[66] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[67-69]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[64] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[70] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[71-75] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[76]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[77-80] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[80] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[81,82] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[74,78,83] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[84] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[85]

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