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Published in Press Release. Daniel is our chief editor and is a man who is loved by all. He is an essential persona and full of life. He loves adventure and has great stories to tell always. He is very sustainable and gives his full attention towards work. Gene product regulation by microRNAs miRNAs in particular is likely to have an important role in both establishment and escape from growth arrest.

In recent years, study of metabolic alterations in cancer cells has regained focus. Metabolic reprogramming is central to cancer formation and progression, and is classically referred to as the Warburg effect. In normal cells, under conditions of normoxia, glucose if fully oxidized to carbon dioxide via the citric acid cycle and mitochondrial oxidative phosphorylation.

This pathway is very efficient in terms of ATP production. Glycolysis, the alternative pathway of glucose metabolism, is less energetically efficient and most normal cells is only used under conditions of hypoxia. Cancer cells, however, preferentially metabolize glucose via glycolysis regardless of oxygen abundance. Specific mediators of metabolic reprogramming in cancer cells are beginning to be understood and their role in nevus and melanoma formation will be considered in this section.

Early studies in senescence and OIS showed that although senescent cells permanently exit from the cell cycle, they maintain metabolic activity. The M2 splice isoform of pyruvate kinase PKM2 has been shown to be preferentially upregulated in cancers and may specifically induce a Warburg metabolism.

PDK1 levels tend to be higher in human nevi than in melanoma, consistent with the hypothesis that oxidative phosphorylation is the predominate means by which glucose is metabolized in nevi. PKM2 levels have not been specifically compared between nevi and melanomas.

On the basis of these observations, it is reasonable to hypothesize that restriction of Warburg metabolism is likely an important factor that limits nevus growth after BRAF mutation; however, how specifically this occurs in nevi remains unclear. C-MYC transcriptional activity is thought to be higher in melanomas than in nevi, consistent with this hypothesis.

Interestingly, although in isolation BRAF VE mutation promotes oxidative phosphorylation, in a fully transformed state, such as melanoma, mutant BRAF alternatively appears to promote glycolysis and support the Warburg effect. Several studies have suggested that autophagy has an important role in OIS. Autophagy is a process by which cellular proteins and organelles can be degraded under unfavorable conditions to generate both energy and macromolecular building blocks.

When autophagy is activated, cellular substrates are encircled by autophagic vesicles and delivered to lysosomes for bulk degredatation. Activation of autophagy has been proposed to promote OIS in part by facilitating the senescence-associated secretory phenotype SASP in senescent cells. For example, autophagy promotes tumor cell survival in the setting of anti-cancer therapy, including during treatment with BRAF-mutant melanomas with BRAF inhibitors.

These seemingly disparate roles for autophagy are perhaps reconcilable if one considers the context in which they occur. For example, a study in mice showed that inactivation of autophagy had opposite effects based on whether or not functional p53 was present.

In this study, when p53 is intact that is, early in tumorigenesis autophagy has a tumor-suppressive function, however, when p53 is lost that is, as later in tumor progression , autophagy alternatively promotes tumor progression. Analysis of human melanocytic lesions supports the hypothesis that autophagy has a context-dependent role.

Immunohistochemical analyses have shown that relative to early melanomas, nevi show increased staining for markers of autophagy including LC3B, Beclin1 and ATG5. Maturation in nevi is discussed above and summarized in Figure 1.

Interestingly, Ivanov et al. However, previous ultrastructural analyses were not able to detect changes in the number of autophagosomes as a function of nevus maturation. Endoplasmic reticulum ER stress occurs in the setting of very high levels of protein translation when misfolded and unfolded proteins accumulate in the ER, leading to an unfolded protein response UPR.

In , Denoyelle et al. In this study, although evidence of sustained ER stress was noted in Spitz nevi, it was not evident in more typical acquired nevi. Subsequent analysis of melanocytic lesions using GRP78, a marker of ER stress, showed low levels of ER stress in nevi, but much higher levels in melanoma. A major difference between in vivo and in vitro systems is the presence or absence of a physiologic microenvironment. In vivo , the tissue microenvironment consists of multiple cellular and non-cellular entities, which directly and indirectly interact with melanocytes and undoubtedly influence their behavior.

It can be hypothesized that features of nevi observed in tissue, but not in growth-arrested BRAF -mutant melanocytes in culture, such as nesting and maturation, may be a reflection of interactions among nevus melanocytes and with the tissue microenvironment Figure 1. During maturation, melanocytes become smaller, less pigmented and change their shape. Further, within nests themselves, melanocytes at the edges of the nest tend to be smaller, whereas those centrally tend to be larger. These patterns suggest that the phenotype of an individual melanocyte is influenced by its position within the nevus and within in the skin.

The specific factors regulating nesting and maturation are difficult to study and not well understood. In terms of maturation, a study by Perez et al. Extracellular matrix composition is thought to vary significantly between nevi and melanomas, however the specific factors which influence nevus nesting and maturation are not known. The likely importance of nesting and maturation in tumor suppression is underscored by the observation that in melanoma these features tend to be disrupted.

In fact, patterns of nesting and maturation are key histologic features used by dermatopathologists to distinguish nevi from melanoma in biopsy specimens. Similarly, maturation is lost in melanoma. Although the factors that mediate these processes are poorly understood, they are likely to have an important role in nevus formation, and at least in part, reflect a regulatory influence of the tissue microenvironment.

In skin biopsies, both normal individual melanocytes, as well as nevus melanocytes appear to prefer to be in close association with keratinocytes. Melanocytes in tissue tend to be concentrated in areas adjacent to both basal interfollicular and follicular keratinocytes. This observation also appears to be true in vitro also. Cultured melanocytes prefer to be associated with and grow better in association with keratinocytes.

For this, reason a keratinocyte feeder layer is often used in the culture of melanocytes. Nevus melanocytes likely interact with other cells in their microenvironment actively through secreted molecules. SASP has even been proposed to activate immune surveillance of lesions in tissue. In terms of secreted inflammatory mediators, upregulation of IL-6 and IL-8 have been shown to occur after BRAF activation in vitro and are thought to reinforce senescence in a cell autonomous manner.

In human tissue, both IL-1 and IL-6 are upregulated in benign nevi relative to dysplastic nevi and melanoma. The role of the immune system in suppression of melanocytic neoplasia will be the focus of the following section. The immune system likely has a role in controlling growth of nevi and preventing progression to melanoma. The ability of the immune system to interact with melanocytes in a functionally relevant manner is supported by several clinical observations.

For example, vitiligo is a condition characterized by complete loss of melanocytes in affected areas of skin leading to the formation of depigmented patches. Melanoma is associated with a relatively high mutation burden and is considered an immunogenic cancer.

An additional informative clinical observation from patients relates to immunosuppression. Immunosuppressed patients such as solid organ transplant recipients and patients with chronic lymphocytic leukemia have an approximately twofold increased incidence of invasive melanoma compared with non-immunosuppressed individuals. Importantly, though, the increased risk of melanoma in immunosuppressed patients is relatively modest compared with some other malignancies.

For example, solid organ transplant recipeints have a 65—fold increased risk of developing cutaneous squamous cell carcinoma. Matin et al. However, the relative proportion of nevi developing from nevi versus de novo in transplant recipients has not been specifically studied and is already known to be highly variable between different studies.

Some murine models have shown that in certain circumstances, cells with senescence phenotypes can be recognized and eliminated by both innate and adaptive arms of the immune system, — however, this has not specfically been studied in nevi. In tissue, banal acquired nevi tend to be relatively pauci-inflammatory in contrast to melanomas, which in general show more robust lymphocytic infiltration.

Regression is a histologic phenomenon observed in some early melanomas and is characterized by focal areas of apparent tumor cell loss and replacement by fibrosis and inflammation. Regression is typically not observed in nevi other than the outer perimeter of halo nevi. The generally accepted view is that regression reflects prior immune-mediated destruction of a portion of the melanoma, however, this is based mainly on inference from the clinical and histological appearance of regressed melanomas.

Interestingly, the T cells found in areas of regression actually differ from the T cells in conditions such as vitiligo and halo nevi. The significance of this observation is unclear. An alternative hypothesis to explain regression is that tumor cell loss is instead driven by genomic crisis occuring in incipient melanomas and leading to apoptosis — this hypothesis will be discussed further below.

Recently, type I interferon signaling was also shown to have a tumor-suppressive role in the Braf VE mouse model. The tumor-suppressive effect of interferon signaling in this model appeared to be partially melanocyte autonomous and partially melanocyte non-autonomous, suggesting one possibility is that interferon could stimulate immune surveillance of nevus melanocytes, however, this was not specifically studied. Interestingly, previous work has shown that secretion of type I interferon by senescent cells is mediated by activation of the DNA damage response.

The complex interplay between the immune system and neoplastic cells is underscored by the observation that chronic inflammation, can alternatively promote tumorigenesis over time. Telomeres are protective structures at the ends of chromosomes formed by a repetitive DNA sequence and an associated protein complex shelterin.

The DNA portion of telomeres becomes progressively shorter after each round of cell division and upon reaching a critically shortened length triggers RS as discussed above. In , it was reported that the promoter of the telomere reverse transcriptase TERT is mutated at very high frequencies in melanomas, but not in nevi. Nevi have been shown to have absent or relatively low telomerase expression, but in melanoma telomerase is commonly expressed at relatively high levels, especially in advanced lesions.

TERT promoter mutations have been shown to be associated with increased telomerase expression in melanoma. In the context of these observations, one might predict that TERT promoter mutations provide a selective advantage in advanced melanomas, but might have relatively less important role in nevi and in situ melanomas. However, recent findings by Shain et al. One hypothesis to reconcile these seemingly disparate observations is that although telomeres are not critically shortened in nevi, they become so during the transition to melanoma.

Along these lines, Bastian and colleagues have proposed that histologic regression observed in early melanomas as discussed above reflects the aftermath of a catastrophic genetic event that is initiated by critical telomere shortening. In this hypothetical model, melanocytic subpopulations of incipient melanomas that are not able to overcome genetic stress induced by critical telomere shortening undergo apoptosis, resulting in the loss of areas of neoplastic melanocytes.

In this model, melanocytes in nevi would be predicted to slowly replicate overtime leading to critical telomere shortening that drives disappearance of nevi after RS. Although intriguing, to date, there is little experimental evidence to directly support this hypothesis. An alternative hypothesis is that TERT expression provides a telomere-independent function that is important in early stages of melanomagenesis.

The importance of telomere biology in melanocytic neoplasia is underscored by the observation that inherited mutations conferring an increased risk of melanoma cluster on genes that encode components of the telomere shelterin complex, in addition to TERT itself. Functional data from murine models and observations in human lesions strongly implicate PTEN in restricting BRAF VE -induced melanomagenesis in vivo ; perhaps more convincingly that any other proposed mechanism of growth arrest after BRAF activation in melanocytes.

These pathways are highly conserved and are typically activated downstream of receptor tyrosine kinases, but are also regulated by sensors of intracellular conditions. When activated via mutation, this pathway provides a constitutive cellular growth signal. Tumor suppressors: red, oncogenic effect: blue. RTK, receptor tyrosine kinase. As discussed above, Braf VE mutation alone induces formation of mouse nevi, but rarely melanoma, even with long latency. Data published by Vredeveld and colleagues supports and extends this hypothesis.

They show that that Pten depletion in already established Braf VE -induced nevi using an shRNA approach also results in melanoma formation. Analysis of human lesions also supports the important role of PTEN in restricting melanoma formation. Immunohistochemical staining for PTEN tends to be strong and uniform in melanocytic nevi. For example, Cdk4 was recently shown to control cellular glucose uptake in addition to cell cycle control.

This work uncovered an unanticipated epigenetic checkpoint that regulates full mTOR activation in the progression of nevi to melanoma. The oncogenic role of Rictor in human melanoma is supported by the observation that the RICTOR gene is frequently amplified in melanoma. Analysis of human melanocytic lesions supports the hypothesis that activation of both mTORC1 and mTORC2 are important in melanoma, as the activity of both complexes tends to be relatively low in in nevi, but high in melanoma.

For example, activation of mTORC1 substrates such as ribosomal protein S6 are only rarely present in nevi, but frequent in human melanomas. Although the exact reason why concurrent activation is required for a fully malignant phenotype is not completely clear, it has been hypothesized to relate in part to metabolic reprogramming of tumor cells. Pten loss in our murine models does not induce analagous melanocyte proliferation in isolation. Separate work has suggested that alternatively mTORC1 may become increasingly activated in senescent cells and may help enforce senescence phenotypes through activation of SASP.

The possible sequence and differential contribution of various mutations, as recently described by Shain and colleagues, is discussed below. The above discussion has largely focused on banal acquired melanocytic nevi, lesions for which most, if not all, dermatopathologists would agree on the diagnosis based on histologic grounds.

Other melanocytic lesions are not as clear cut and can have some features of melanoma and some features of nevi, either clinically, histologically, or both; creating a diagnostic gray zone. Dysplastic and atypical nevi are terms used by clinicians to describe lesions with concerning histologic or clinical features, respectively. As part of clinical practice, histologically dysplastic nevi are often graded based on the degree abnormality into categories of mild, moderate and severe dysplasia; with severe dysplasia bordering on melanoma, but not quite meeting diagnostic criteria.

This system of grading histologic dysplasia and its implications are controversial because of a lack of consensus terminology and disagreement over clinical management of these lesions. Further, this grading system implies that progression through different degrees of dysplasia toward melanoma occurs in a linear, progressive fashion.

For example, it is not known what proportion of dysplastic nevi develop de novo versus what percentage could represent evolution of previously banal nevi. It should be noted that in the vast majority of cases, definitive histological features of banal nevi and dysplastic nevi are not observed in the same lesion, suggesting progression from one to the other is probably rare. The relationship of dysplastic nevi to melanoma is also incompletely understood. For example, it is unclear if individual dysplastic nevi progress to melanoma at higher rates than banal nevi.

In fact, this seemingly straight forward question is difficult to study directly as to establish a diagnosis of dysplasia, the lesion must be biopsied usually fully removed. Further, clinical aytpia does not necessarily correlate with histologic dysplasia, suggesting these lesions cannot reliably be identified clinically and followed.

Several studies have indirectly addressed this question by comparing the frequency with which melanomas are associated with the remnants of banal nevi versus the remnants dysplastic nevi. A recent study by Shain et al. In this excellent work, the authors also address the sequence in which mutations are likely to have occurred. Despite these observations by Shain and colleagues, however, it is still not clear that histologically dysplastic lesions have an increased risk of progression to melanoma compared to their banal counterparts, they may just be more morphologically similar to melanoma histologically.

Further work will be required to better characterize the relationship among benign nevi, histologically dysplastic nevi and melanoma. Despite the controversy in this area, a history of a histologically dysplastic nevus is still clinically significant for patients.

At a population level, patients with a history of nevi with increasing histologic dysplasia carry a dose-dependent increase in the overall risk of developing melanoma. It is unclear if this increased risk is related to exposure to mutagens such as ultraviolet light, an inherent genetic susceptibility to melanocytic neoplasia, or a combination of both. OIS is a paradigm that has been used to understand growth arrest after oncogene activation and has significantly advanced our understanding of neoplasia broadly, including the importance of cooperation between multiple oncogenes in cancer.

However, this terminology is slightly confusing when applied to melanocytic lesions in tissue, as although cells express some markers of senescence, overall they appear to have relatively few phenotypic features of senescent cells as discussed above. In fact, in Tran et al. Mechanisms of growth arrest during stable clonal expansion.

After acquisition of individual oncogenic mutations BRAF VE , growth arrest of melanocytic nevi is established and maintained by multiple different, overlapping mechanisms. Progression to melanoma likely requires simultaneous abrogation of multiple growth suppressive pathways. Several clinical observations suggest that nevi are not static senescent , even after they reach a seemingly final size.

For example, although the majority of nevi do appear to remain relatively stable in size over time, a subset will enlarge. In clinical practice, when enlarging nevi are noted, they are typically biopsied to evaluate for melanoma. But, does enlargement of nevi necessarily mean that growth arrest mechanisms have been bypassed and progression to melanoma has occurred; as would be implied based on the OIS hypothesis?

To address this question, Lucas and colleagues carefully tracked individual nevi over time in adults using total body photography and biopsied lesions that had changed appearance including increased in size. They found that increase in size alone in otherwise non-concerning lesions rarely led to a diagnosis of melanoma. Interestingly, nevi can change appearance in other settings, such as during pregnancy and after exposure to ultraviolet radiation, changes that do not necessarily signify progression to melanoma.

For example, in pregnant patients, nevi can change color, dermatoscopic appearance, , increase in size , and show increased mitotic rates. Exposure to ultraviolet radiation induces proliferation of nevus cells, , yet this proliferation does not equate to melanoma formation. In other words, nevi appear to maintain the ability to respond physiologically to various stimuli, including increasing proliferation rates while maintaining their benignity and stability of growth arrest.

Additional observations suggest that, in fact, nevus melanocytes actually retain significant proliferative potential. For example, nevi can regrow in patients when only partially biopsied incompletely removed and are known as recurrent nevi. In recurrent nevi, nevi regrow to a similar size within the scar at the biopsy site, but then again stop clinical growth and remain benign.

In several reports from the s, it was shown that nevus melanocytes derived from clinical specimens can proliferate in culture, where they actually proliferate faster than normal melanocytes grown under the same conditions. In fact, close histologic examination of nevi shows that even common banal nevi have mitotically active melanocytes, which are present at low, but reproducible rates. Using Ki67, a marker of actively cycling cells, Soyer et al.

In nevi, proliferative activity is generally restricted to the most superficial portions of the lesion — Figure 1. If the above estimates are correct, and melanocytes in nevi do slowly divide over time, then melanocyte attrition would be need to be present at a similar rate to maintain a relatively stable size over time.

Along these lines, low rates of apoptosis have also been reported in melanocytic nevi. Interestingly, contrary to mitotic activity, which tends to favor the superficial portion of the lesion, apoptotic cells predominate in deeper portions of the dermis and are almost never found in superficial portions of the lesion. However, to date there is no experimental evidence to support this hypothesis. Shain et al. In this model, eventual telomere crisis, RS, and subsequent clearance of nevus melanocytes might mechanistically underlie the observed clinical regression of nevi with advancing age.

Overall, these observations suggest that although nevi demonstrate tremendous clinical stability, behind the scenes nevus melanocytes are seemingly fairly dynamic. Microscopically low rates of proliferation are balanced by cell attrition. Nevus melanocytes can respond to environmental stimuli and even increase their proliferation without transforming to melanoma.

Stable clonal expansion is maintained by multiple, overlapping, nearly fail-safe mechanisms including pathway intrinsic and extrinsic feedback loops, epigenetic reprogramming, microenvironmental effects, metabolic constraints and others Figure 6. These mutant clones provide local selective advantage and ultimately result in formation of a quilt-like pattern of partially overlapping, competing clones. These results are important as they show that despite the presence of potent oncogenic mutations, normal cellular function and tissue viability including proliferation is maintained.

Constitutive proliferation of keratinocytes is required to continuously turnover skin and maintain epidermal barrier function; a process that seemingly proceeds undisturbed within mutant clones. In keratinocytes at least, a tumor-suppressive response that involved complete and irreversible withdrawal from the cell cycle would be predicted to result in disappearance of the clone over time.

Applied to melanocytes and other cell types, these observations suggest that despite oncogenes which result in clonal expansion, typical cellular function can be maintained. This principle is likely to be important in other tissue types, even those not constantly exposed to a potent mutagen like ultraviolet light. Even in the absence of an outside mutagen, cells are constantly exposed to new oncogenic insults generated during DNA replication.

For example, Chandeck and Mooi estimate based on organism wide rates of cell division in humans 5 million every second and the inherent imperfection in DNA replication which leads to an unrepaired point mutation in 1 out of every 1 billion replicated bases, that by chance activating mutations occurring in any given oncogene for example, BRAF VE occur approximately every 10 min somewhere in the body. The importance of this effect is underscored by the more recent observation that differential rates of cancer development in different tissue types correlates with the frequency with which stem cells divide in that tissue.

This presumably incidentally leads to enhanced generation of mutant oncogenes, which persist in stem cell populations. Taking these various considerations together, we favor the term stable clonal expansion when referring to melanocytic nevi in tissue, rather than oncogene-induced senescence. To us, this term better reflects nevus phenotypes observed in mouse models and in human lesions.

In nevi, despite stable lesion size clinically, the melanocytes in nevi are dynamic and multiple cooperative cell intrinsic and extrinsic factors restrain continuous growth Figure 6. However, this process can be overcome as part of progression to melanoma, with the acquisition of additional pathogenic mutations and failure of a critical mass of growth suppressive programs.

National Center for Biotechnology Information , U. Author manuscript; available in PMC May 2. WE Damsky 1 and M Bosenberg 1, 2. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Oncogene. See other articles in PMC that cite the published article. Clinical and histopathologic features Nevi are most often 2—6 mm in size and have a uniform color and symmetric architecture clinically. Open in a separate window.

Figure 1. Figure 2. Figure 3. Figure 4. Epigenetics Epigenetics broadly refers to chromosomal alterations that affect processes such as gene expression, but do not change the actual DNA sequence. Cellular metabolism In recent years, study of metabolic alterations in cancer cells has regained focus. Autophagy and endoplasmic reticulum stress Several studies have suggested that autophagy has an important role in OIS. Microenvironmental mediators A major difference between in vivo and in vitro systems is the presence or absence of a physiologic microenvironment.

Role of the immune surveillance The immune system likely has a role in controlling growth of nevi and preventing progression to melanoma. The role of telomeres Telomeres are protective structures at the ends of chromosomes formed by a repetitive DNA sequence and an associated protein complex shelterin.

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Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV mutations. Expert Opin Pharmacother. A negative feedback signaling network underlies oncogene-induced senescence. The developing story of Sprouty and cancer. Cancer Metastasis Rev. The genetic evolution of melanoma from precursor lesions.

The molecular balancing act of p16 INK4a in cancer and aging. Mol Cancer Res. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. ARF tumor suppression in the nucleolus. Biochim Biophys Acta. Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Analysis of the p16 gene CDKN2 as a candidate for the chromosome 9p melanoma susceptibility locus. Cutaneous melanoma susceptibility and progression genes.

Cancer Lett. Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. Int J Cancer. Radhi JM. Malignant melanoma arising from nevi, p53, p16, and Bcl expression in benign versus malignant components. J Cutan Med Surg. Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous melanocytic tumors.

Int J Surg Pathol. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep. Nucleotide deficiency promotes genomic instability in early stages of cancer development.

Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene-induced senescence. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.

Absence of distinguishing senescence traits in human melanocytic nevi. Expression of gamma-H2AX in melanocytic lesions. Nowsheen S, Yang ES. The intersection between DNA damage response and cell death pathways. Exp Oncol. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. The ultrastructure of benign pigmented naevi and melanocarcinomas in man.

J Pathol. Ultrastructural discrimination between malignant melanomas and benign nevocytic nevi using high-resolution image and multivariate analyses. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi.

Aging Cell. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell. Epigenetic regulation in human melanoma: past and future. Epigenetic silencing of novel tumor suppressors in malignant melanoma. Claudin11 promoter hypermethylation is frequent in malignant melanoma of the skin, but uncommon in nevus cell nevi. Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.

RASSF10 promoter hypermethylation is frequent in malignant melanoma of the skin but uncommon in nevus cell nevi. DNA-methylation profiling distinguishes malignant melanomas from benign nevi. Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance.

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Bad beat: Losing a bet you should have won. It's especially used when the betting result is decided late in the game to change the side that covers the spread. Also used in poker, such as when a player way ahead in the expected win percentage loses on the river last card.

Book: Short for sportsbook or bookmaker; person or establishment that takes bets from customers. Buying points: Some bookies or sportsbooks will allow customers to alter the set line and then adjust odds. For example, a bettor might decide he wants to have his team as a 3-point underdog instead of the set line of 2. He has then "bought" half a point, and the odds of his bet will be changed.

Chalk: The favorite in the game. People said to be "chalk" bettors typically bet the favorite. Consensus pick: Derived from data accumulated from a variety of sportsbooks in PickCenter. The pick, and its percentage, provides insight as to what side the public is taking in a game. Cover: The betting result on a point-spread wager.

For a favorite to cover, it has to win by more than the spread; an underdog covers by winning outright or losing by less than the spread. Edge: An advantage. Sports bettors might feel they have an edge on a book if they think its lines aren't accurate. Exotic: Any wager other than a straight bet or parlay; can also be called a "prop" or "proposition wager. Favorite : The expected straight-up winner in a game or event. Depending on the sport, the favorite will lay either odds or points.

For example, in a football game, if a team is a 2. Fixed : A participant in a particular game who alters the result of that game or match to a completely or partially predetermined result. The participant did not play honestly or fairly because of an undue outside influence.

Futures bet : A long-term wager that typically relates to a team's season-long success. Common futures bets include betting a team to win a championship at the outset of a season, or betting whether the team will win or lose more games than a set line at the start of the season.

Halftime bet : A bet made after the first half ended and before the second half begins football and basketball primarily. Handle : The amount of money taken by a book on an event or the total amount of money wagered. Hedging : Betting the opposing side of your original bet, to either ensure some profit or minimize potential loss. This is typically done with futures bets, but can also be done on individual games with halftime bets or in-game wagering. Hook : A half-point.

In-game wagering : A service offered by books in which bettors can place multiple bets in real time, as the game is occurring. Juice : The commission the bookie or bookmaker takes. Standard is 10 percent. Layoff: Money bet by a sportsbook with another sportsbook or bookmaker to reduce that book's liability. Limit : The maximum bet taken by a book. Middle : When a line moves, a bettor can try to "middle" a wager and win both sides with minimal risk.

Suppose a bettor bets one team as a 2. She can then bet the opposite team at 3. She would then win both sides of the bet. Money line noun , money-line modifier : A bet in which your team only needs to win.

The point spread is replaced by odds. Oddsmaker also linemaker : The person who sets the odds. Some people use it synonymous with "bookmaker" and often the same person will perform the role at a given book, but it can be separate if the oddsmaker is just setting the lines for the people who will eventually book the bets. Off the board : When a book or bookie has taken a bet down and is no longer accepting action or wagers on the game. This can happen if there is a late injury or some uncertainty regarding who will be participating.

Also used in prop bets. Parlay : A wager in which multiple teams are bet, either against the spread or on the money line. The more teams you bet, the greater the odds. Pick 'em : A game with no favorite or underdog. The point spread is zero, and the winner of the game is also the spread winner. Point spread or just "spread" : The number of points by which the supposed better team is favored over the underdog.

Proposition or prop bet : A special or exotic wager that's not normally on the betting board, such as which team will score first or how many yards a player will gain. Sometimes called a "game within a game. Push : When a result lands on the betting number and all wagers are refunded.

For example, a 3-point favorite wins by exactly three points. Square : A casual gambler. Someone who typically isn't using sophisticated reasoning to make a wager. Co-favorite: Two or more sides with identical odds to win. Common with futures odds, bookmakers may post co-favorites to win the NBA Finals championship. Combine: A series of fitness tests that help scouts from professional teams evaluate amateur athletes.

Commission: Another term for vigorish and juice, commission is the bookmakers take on any bet. It is also the amount a betting exchange takes from winning wagers. Correct score: Bettors are offered a list of possible final scores on a match. In soccer, players can bet on a match ending as low as or as high as plus all scores in between. The most likely result is the favorite and the least likely result is the underdog. New England winning over Miami means the Patriots would cover a point spread.

Dog: Short for underdog, a dog is perceived as the least likely side to win and is tagged with plus pricing. Bettors often double their bet when they feel one side is vastly superior to another. Double result: A single betting option that combines the score of a game at halftime and the score at the end of the same game. Double-header: Two games that are played back-to-back on the same day.

Most common in baseball, a double-header will often take place if a game from the previous day was rained out. Draw: Any contest where the final score ends in a tie. In most instances, a draw is graded as a PUSH and original bet amounts are returned. Drift: Betting odds that grow longer after the opening line is posted.

Each-way: Common in horse racing, each-way betting takes a single amount and splits it on a horse to finish first or second. Both bets pay if the horse finishes first while just one bet pays if the horse finishes second. The return on a first place win is always higher than the return on a second place win. Edge: Gaining an advantage through extensive research or having insights that are not publicly known. Even money: Odds that return the exact amount of the original bet. Exotic Bet: Betting options beyond point spreads, moneylines and game totals.

Proposition bets, specials and parlays are the most common types of exotic bets. Exposure: Amount of money a bettor or bookmaker stands to lose on any given wager. Favorite: Any side priced with a negative number. Two Final Four games are played prior to the National Championship game.

First half bet: A wager that focused on the result of the first half in sports like basketball, soccer and football. The most popular first half betting odds are spread, moneyline and game total options. A variety of team and player props are also offered as first half bets. Fixed odds : When a wager is placed, and a bookmaker accepts it, the line becomes fixed odds.

Also a term for moneyline odds. French Open : Second of four women's and men's Grand Slam tennis tournaments that are played over two weeks in late May and early June. Futures bet : A wager placed on an event that will take place in the near or distant future.

Futures are also offered in soccer, major horse races, plus golf and tennis tournaments. If a baseball game total is set at 7. Graded Bet: A wager that bookmakers officially mark as a winner, a loser, or a push, once a competition has ended.

Winnings, or push refunds, are paid out after a bet has been graded. If there are seven games on the NFL schedule, the line may be set at Half ball handicap: Soccer betting odds where 0. Half time bet : Wagers placed on the outcome of just the second half of a competition.

Half time bets can be placed during intermission or as live wagers once the second half begins. Handicap: Betting odds set by a bookmaker that are designed to level the playing field. New Orleans may have a If the Saints win by eight or more points - they cover the handicap and produce winning wagers. Handicapper: A bettor who researches matchups and then places a bet.

Also applies to tipsters who publish predictions on various sporting events. Handle: Total amount of money a bookmaker accepts on a single game or event. Hedge : Most common with parlay betting and as a risk management tool. Hedging a bet consists of betting on the opposite side of an original wager to set up a guaranteed return. A hedge bet may also be placed to reduce the initial risk on a potential losing wager.

Home field advantage: The perceived benefit a team gains when playing in familiar settings at their home stadium. Hook : A half point added to point spreads and game total odds. A hook guarantees a wager will not be graded as a push.

One side will win and one side will lose. If bet: A member of the parlay family, an If Bet consists of two or more wagers. In play betting: Wagers placed after an event after it has started. Also known as LIVE betting, bookmakers post multiple in-play betting options throughout most major sporting events. Joint favorite: Two or more sides posted with the same betting odds on the same event. Juice : Also known as vigorish, juice is set by bookmakers and is attached to spread and total betting options.

If Minnesota Kentucky Derby: First jewel in the Triple Crown of thoroughbred racing. Laying points : Betting on a favorite. A wager on Dallas, as a The Cowboys need to win by at least points to cash a winning ticket.

Layoff: Used by bookmakers and players to reduce risk on a certain market. Parlay bettors may have an option to place a layoff wager on both sides of the last open bet on a ticket to set up a guaranteed profit. Limit: Bookmakers set various high and low wagering limits that vary by sport and betting options. As part of a proper bankroll management system, players should set and follow personal betting limits. Line: Betting odds posted by a bookmaker.

Linemaker: Same as a bookmaker, a person or group that sets daily betting lines and prices. Listed pitchers: Appear with daily baseball betting odds. Live betting : Also known as in-play wagering, live betting is offered once a sporting event begins.

Spreads, moneylines and totals are adjusted and re-posted as a match plays out. Prop options, like next goalscorer and correct final score, are also available. Lock: Term often used by tipsters to tempt bettors into buying handicapping advice. Death and taxes are the only true locks in life. Longshot: A perceived inferior side that is also known as an underdog. Longshot prices are always displayed as positive prices. Masters Tournament: First of four major Grand Slam golf tournaments.

Middle : Cashing tickets on both sides of a betting option. Bettors have an opportunity to middle when a point spread moves up or down prior to a match. The MLB draft is five rounds and most of the players selected will be assigned to minor league teams. Moneyline : A straight up bet, without any point spread, where bettors need to predict the outright winner. Multiple bets: Same as parlay, multiple bets are a single wager that consists of at least two sides on a single ticket.

All sides must win or push to cash winning multiple bets. MVP: Player honored as most valuable to their team during the regular season or playoffs. Wagering on who will be named the Most Valuable Player is a popular futures betting option in professional sports. Nap: Similar to a lock, a nap is a handicappers suggested best bet on a daily betting card. No action: Betting options cancelled by a bookmaker are graded as no action.

Original stakes are returned to bettors. Novelty bets: Prop and special betting options that are wagers beyond standard moneyline, point spread and game total odds. Team and player propositions are the most common novelty bets. Odds: Betting lines set by a bookmaker on a variety of events. Oddsmaker: Same as a linemaker, a person or group that sets daily betting lines and prices. Odds on favorite: One side that is viewed as far superior to the other and is priced with odds that offer very little value.

Odds shopping: Reviewing the lines at a variety of sportsbooks in order to find the best priced odds. An injury to a star player may cause bookmakers to pull odds off the board. Outright betting: Predicting the overall winner of a tournament or playoff competition. Over bet: Opposite of an Under bet on game total options. Bettors need to determine if the combined scores of both teams will go over or remain under the number.

Also known as game total odds. Parlay : A single bet, also known as an accumulator or multiple, that consists of two or more sides. Each side must win to produce a winning ticket. Parlay banker: Forming the base of a parlay wager, a banker is a favorite side to which other sides are added. Payout: The amount a bettor collects on a winning wager.

When a wager is placed, the possible payout on a betting receipt usually includes the original stake. Held in late May at various courses across the United States. Point spread : Odds posted on a match that are designed to level the playing field.

Favorites are listed with a negative Post time: Scheduled start time of a race. Power rankings: A ranking system that uses a variety of criteria to grade teams, in a specific league, from the best to worst. Preakness Stakes: Second jewel in the Triple Crown of thoroughbred racing.

Proposition bet: Often shortened to prop bet, proposition bets are exotic or special wagers that are offered on most sporting events. NFL Super Bowl prop betting options number in the hundreds. Proxy : A proxy is an individual, or a group of individuals, who place bets for other people. The term is most commonly associated with people who submit picks for non-Las Vegas residents that are involved in season-long sports pools like the Westgate Las Vegas SuperContest.

Puck line: Point spread pricing in hockey. Prior to a match, the favorite is normally posted at Push: Any wager where the final result is a tie. If a basketball spread is 11 points and the final score is spread bets on both teams are graded as a push and original stakes are returned. Quarter Bet : Any wager placed prior to or during any quarter of a sporting event. Prior to an NBA game, Boston may be a LIVE betting odds will change often as the first 12 minutes of the match play out.

Recreational Bettor: A player that bets infrequently or on major sporting events only. Rec player bets are counted as public money. Opposite of a sharp or professional bettor. Rotation Number: A number assigned by bookmakers to every betting option on the board. Bettors use the rotation number when placing a bet, rather than team names, at betting windows at land based sportsbooks. ROY: Honors the top first year player in most professional sports leagues.

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Published in Press Release. However, the relative proportion of nevi developing from nevi versus de novo in transplant recipients has not been specifically studied and is already known to be highly variable between different studies. Some murine models have shown that in certain circumstances, cells with senescence phenotypes can be recognized and eliminated by both innate and adaptive arms of the immune system, — however, this has not specfically been studied in nevi.

In tissue, banal acquired nevi tend to be relatively pauci-inflammatory in contrast to melanomas, which in general show more robust lymphocytic infiltration. Regression is a histologic phenomenon observed in some early melanomas and is characterized by focal areas of apparent tumor cell loss and replacement by fibrosis and inflammation. Regression is typically not observed in nevi other than the outer perimeter of halo nevi.

The generally accepted view is that regression reflects prior immune-mediated destruction of a portion of the melanoma, however, this is based mainly on inference from the clinical and histological appearance of regressed melanomas.

Interestingly, the T cells found in areas of regression actually differ from the T cells in conditions such as vitiligo and halo nevi. The significance of this observation is unclear. An alternative hypothesis to explain regression is that tumor cell loss is instead driven by genomic crisis occuring in incipient melanomas and leading to apoptosis — this hypothesis will be discussed further below. Recently, type I interferon signaling was also shown to have a tumor-suppressive role in the Braf VE mouse model.

The tumor-suppressive effect of interferon signaling in this model appeared to be partially melanocyte autonomous and partially melanocyte non-autonomous, suggesting one possibility is that interferon could stimulate immune surveillance of nevus melanocytes, however, this was not specifically studied. Interestingly, previous work has shown that secretion of type I interferon by senescent cells is mediated by activation of the DNA damage response. The complex interplay between the immune system and neoplastic cells is underscored by the observation that chronic inflammation, can alternatively promote tumorigenesis over time.

Telomeres are protective structures at the ends of chromosomes formed by a repetitive DNA sequence and an associated protein complex shelterin. The DNA portion of telomeres becomes progressively shorter after each round of cell division and upon reaching a critically shortened length triggers RS as discussed above. In , it was reported that the promoter of the telomere reverse transcriptase TERT is mutated at very high frequencies in melanomas, but not in nevi.

Nevi have been shown to have absent or relatively low telomerase expression, but in melanoma telomerase is commonly expressed at relatively high levels, especially in advanced lesions. TERT promoter mutations have been shown to be associated with increased telomerase expression in melanoma. In the context of these observations, one might predict that TERT promoter mutations provide a selective advantage in advanced melanomas, but might have relatively less important role in nevi and in situ melanomas.

However, recent findings by Shain et al. One hypothesis to reconcile these seemingly disparate observations is that although telomeres are not critically shortened in nevi, they become so during the transition to melanoma. Along these lines, Bastian and colleagues have proposed that histologic regression observed in early melanomas as discussed above reflects the aftermath of a catastrophic genetic event that is initiated by critical telomere shortening.

In this hypothetical model, melanocytic subpopulations of incipient melanomas that are not able to overcome genetic stress induced by critical telomere shortening undergo apoptosis, resulting in the loss of areas of neoplastic melanocytes. In this model, melanocytes in nevi would be predicted to slowly replicate overtime leading to critical telomere shortening that drives disappearance of nevi after RS.

Although intriguing, to date, there is little experimental evidence to directly support this hypothesis. An alternative hypothesis is that TERT expression provides a telomere-independent function that is important in early stages of melanomagenesis. The importance of telomere biology in melanocytic neoplasia is underscored by the observation that inherited mutations conferring an increased risk of melanoma cluster on genes that encode components of the telomere shelterin complex, in addition to TERT itself.

Functional data from murine models and observations in human lesions strongly implicate PTEN in restricting BRAF VE -induced melanomagenesis in vivo ; perhaps more convincingly that any other proposed mechanism of growth arrest after BRAF activation in melanocytes. These pathways are highly conserved and are typically activated downstream of receptor tyrosine kinases, but are also regulated by sensors of intracellular conditions.

When activated via mutation, this pathway provides a constitutive cellular growth signal. Tumor suppressors: red, oncogenic effect: blue. RTK, receptor tyrosine kinase. As discussed above, Braf VE mutation alone induces formation of mouse nevi, but rarely melanoma, even with long latency. Data published by Vredeveld and colleagues supports and extends this hypothesis.

They show that that Pten depletion in already established Braf VE -induced nevi using an shRNA approach also results in melanoma formation. Analysis of human lesions also supports the important role of PTEN in restricting melanoma formation.

Immunohistochemical staining for PTEN tends to be strong and uniform in melanocytic nevi. For example, Cdk4 was recently shown to control cellular glucose uptake in addition to cell cycle control. This work uncovered an unanticipated epigenetic checkpoint that regulates full mTOR activation in the progression of nevi to melanoma.

The oncogenic role of Rictor in human melanoma is supported by the observation that the RICTOR gene is frequently amplified in melanoma. Analysis of human melanocytic lesions supports the hypothesis that activation of both mTORC1 and mTORC2 are important in melanoma, as the activity of both complexes tends to be relatively low in in nevi, but high in melanoma. For example, activation of mTORC1 substrates such as ribosomal protein S6 are only rarely present in nevi, but frequent in human melanomas.

Although the exact reason why concurrent activation is required for a fully malignant phenotype is not completely clear, it has been hypothesized to relate in part to metabolic reprogramming of tumor cells. Pten loss in our murine models does not induce analagous melanocyte proliferation in isolation. Separate work has suggested that alternatively mTORC1 may become increasingly activated in senescent cells and may help enforce senescence phenotypes through activation of SASP.

The possible sequence and differential contribution of various mutations, as recently described by Shain and colleagues, is discussed below. The above discussion has largely focused on banal acquired melanocytic nevi, lesions for which most, if not all, dermatopathologists would agree on the diagnosis based on histologic grounds.

Other melanocytic lesions are not as clear cut and can have some features of melanoma and some features of nevi, either clinically, histologically, or both; creating a diagnostic gray zone. Dysplastic and atypical nevi are terms used by clinicians to describe lesions with concerning histologic or clinical features, respectively.

As part of clinical practice, histologically dysplastic nevi are often graded based on the degree abnormality into categories of mild, moderate and severe dysplasia; with severe dysplasia bordering on melanoma, but not quite meeting diagnostic criteria. This system of grading histologic dysplasia and its implications are controversial because of a lack of consensus terminology and disagreement over clinical management of these lesions.

Further, this grading system implies that progression through different degrees of dysplasia toward melanoma occurs in a linear, progressive fashion. For example, it is not known what proportion of dysplastic nevi develop de novo versus what percentage could represent evolution of previously banal nevi. It should be noted that in the vast majority of cases, definitive histological features of banal nevi and dysplastic nevi are not observed in the same lesion, suggesting progression from one to the other is probably rare.

The relationship of dysplastic nevi to melanoma is also incompletely understood. For example, it is unclear if individual dysplastic nevi progress to melanoma at higher rates than banal nevi. In fact, this seemingly straight forward question is difficult to study directly as to establish a diagnosis of dysplasia, the lesion must be biopsied usually fully removed.

Further, clinical aytpia does not necessarily correlate with histologic dysplasia, suggesting these lesions cannot reliably be identified clinically and followed. Several studies have indirectly addressed this question by comparing the frequency with which melanomas are associated with the remnants of banal nevi versus the remnants dysplastic nevi.

A recent study by Shain et al. In this excellent work, the authors also address the sequence in which mutations are likely to have occurred. Despite these observations by Shain and colleagues, however, it is still not clear that histologically dysplastic lesions have an increased risk of progression to melanoma compared to their banal counterparts, they may just be more morphologically similar to melanoma histologically.

Further work will be required to better characterize the relationship among benign nevi, histologically dysplastic nevi and melanoma. Despite the controversy in this area, a history of a histologically dysplastic nevus is still clinically significant for patients. At a population level, patients with a history of nevi with increasing histologic dysplasia carry a dose-dependent increase in the overall risk of developing melanoma.

It is unclear if this increased risk is related to exposure to mutagens such as ultraviolet light, an inherent genetic susceptibility to melanocytic neoplasia, or a combination of both. OIS is a paradigm that has been used to understand growth arrest after oncogene activation and has significantly advanced our understanding of neoplasia broadly, including the importance of cooperation between multiple oncogenes in cancer. However, this terminology is slightly confusing when applied to melanocytic lesions in tissue, as although cells express some markers of senescence, overall they appear to have relatively few phenotypic features of senescent cells as discussed above.

In fact, in Tran et al. Mechanisms of growth arrest during stable clonal expansion. After acquisition of individual oncogenic mutations BRAF VE , growth arrest of melanocytic nevi is established and maintained by multiple different, overlapping mechanisms. Progression to melanoma likely requires simultaneous abrogation of multiple growth suppressive pathways.

Several clinical observations suggest that nevi are not static senescent , even after they reach a seemingly final size. For example, although the majority of nevi do appear to remain relatively stable in size over time, a subset will enlarge. In clinical practice, when enlarging nevi are noted, they are typically biopsied to evaluate for melanoma. But, does enlargement of nevi necessarily mean that growth arrest mechanisms have been bypassed and progression to melanoma has occurred; as would be implied based on the OIS hypothesis?

To address this question, Lucas and colleagues carefully tracked individual nevi over time in adults using total body photography and biopsied lesions that had changed appearance including increased in size. They found that increase in size alone in otherwise non-concerning lesions rarely led to a diagnosis of melanoma.

Interestingly, nevi can change appearance in other settings, such as during pregnancy and after exposure to ultraviolet radiation, changes that do not necessarily signify progression to melanoma. For example, in pregnant patients, nevi can change color, dermatoscopic appearance, , increase in size , and show increased mitotic rates. Exposure to ultraviolet radiation induces proliferation of nevus cells, , yet this proliferation does not equate to melanoma formation.

In other words, nevi appear to maintain the ability to respond physiologically to various stimuli, including increasing proliferation rates while maintaining their benignity and stability of growth arrest. Additional observations suggest that, in fact, nevus melanocytes actually retain significant proliferative potential.

For example, nevi can regrow in patients when only partially biopsied incompletely removed and are known as recurrent nevi. In recurrent nevi, nevi regrow to a similar size within the scar at the biopsy site, but then again stop clinical growth and remain benign. In several reports from the s, it was shown that nevus melanocytes derived from clinical specimens can proliferate in culture, where they actually proliferate faster than normal melanocytes grown under the same conditions.

In fact, close histologic examination of nevi shows that even common banal nevi have mitotically active melanocytes, which are present at low, but reproducible rates. Using Ki67, a marker of actively cycling cells, Soyer et al.

In nevi, proliferative activity is generally restricted to the most superficial portions of the lesion — Figure 1. If the above estimates are correct, and melanocytes in nevi do slowly divide over time, then melanocyte attrition would be need to be present at a similar rate to maintain a relatively stable size over time. Along these lines, low rates of apoptosis have also been reported in melanocytic nevi. Interestingly, contrary to mitotic activity, which tends to favor the superficial portion of the lesion, apoptotic cells predominate in deeper portions of the dermis and are almost never found in superficial portions of the lesion.

However, to date there is no experimental evidence to support this hypothesis. Shain et al. In this model, eventual telomere crisis, RS, and subsequent clearance of nevus melanocytes might mechanistically underlie the observed clinical regression of nevi with advancing age. Overall, these observations suggest that although nevi demonstrate tremendous clinical stability, behind the scenes nevus melanocytes are seemingly fairly dynamic.

Microscopically low rates of proliferation are balanced by cell attrition. Nevus melanocytes can respond to environmental stimuli and even increase their proliferation without transforming to melanoma. Stable clonal expansion is maintained by multiple, overlapping, nearly fail-safe mechanisms including pathway intrinsic and extrinsic feedback loops, epigenetic reprogramming, microenvironmental effects, metabolic constraints and others Figure 6.

These mutant clones provide local selective advantage and ultimately result in formation of a quilt-like pattern of partially overlapping, competing clones. These results are important as they show that despite the presence of potent oncogenic mutations, normal cellular function and tissue viability including proliferation is maintained. Constitutive proliferation of keratinocytes is required to continuously turnover skin and maintain epidermal barrier function; a process that seemingly proceeds undisturbed within mutant clones.

In keratinocytes at least, a tumor-suppressive response that involved complete and irreversible withdrawal from the cell cycle would be predicted to result in disappearance of the clone over time. Applied to melanocytes and other cell types, these observations suggest that despite oncogenes which result in clonal expansion, typical cellular function can be maintained.

This principle is likely to be important in other tissue types, even those not constantly exposed to a potent mutagen like ultraviolet light. Even in the absence of an outside mutagen, cells are constantly exposed to new oncogenic insults generated during DNA replication. For example, Chandeck and Mooi estimate based on organism wide rates of cell division in humans 5 million every second and the inherent imperfection in DNA replication which leads to an unrepaired point mutation in 1 out of every 1 billion replicated bases, that by chance activating mutations occurring in any given oncogene for example, BRAF VE occur approximately every 10 min somewhere in the body.

The importance of this effect is underscored by the more recent observation that differential rates of cancer development in different tissue types correlates with the frequency with which stem cells divide in that tissue. This presumably incidentally leads to enhanced generation of mutant oncogenes, which persist in stem cell populations.

Taking these various considerations together, we favor the term stable clonal expansion when referring to melanocytic nevi in tissue, rather than oncogene-induced senescence. To us, this term better reflects nevus phenotypes observed in mouse models and in human lesions. In nevi, despite stable lesion size clinically, the melanocytes in nevi are dynamic and multiple cooperative cell intrinsic and extrinsic factors restrain continuous growth Figure 6. However, this process can be overcome as part of progression to melanoma, with the acquisition of additional pathogenic mutations and failure of a critical mass of growth suppressive programs.

National Center for Biotechnology Information , U. Author manuscript; available in PMC May 2. WE Damsky 1 and M Bosenberg 1, 2. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Oncogene.

See other articles in PMC that cite the published article. Clinical and histopathologic features Nevi are most often 2—6 mm in size and have a uniform color and symmetric architecture clinically. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Epigenetics Epigenetics broadly refers to chromosomal alterations that affect processes such as gene expression, but do not change the actual DNA sequence.

Cellular metabolism In recent years, study of metabolic alterations in cancer cells has regained focus. Autophagy and endoplasmic reticulum stress Several studies have suggested that autophagy has an important role in OIS. Microenvironmental mediators A major difference between in vivo and in vitro systems is the presence or absence of a physiologic microenvironment.

Role of the immune surveillance The immune system likely has a role in controlling growth of nevi and preventing progression to melanoma. The role of telomeres Telomeres are protective structures at the ends of chromosomes formed by a repetitive DNA sequence and an associated protein complex shelterin. Figure 5. Figure 6. References 1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res.

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