Molecular Pathology of Cutaneous Squamous Cell Carcinoma: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Dermatology
Contributor:
Elena-Codruta Cozma
,
Laura Madalina Banciu
,
Cristina Soare
,
Sanda-Maria Cretoiu

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, originating from keratinocytes of the spinous layer. Numerous risk factors have been discovered for the initiation and growth of this type of cancer, such as exposure to UV and ionizing radiation, chemical carcinogens, the presence of immunosuppression states, chronic inflammation, infections with high-risk viral strains, and, last but not least, the presence of diseases associated with genetic alterations. The important socio-economic impact, as well as the difficulty associated with therapy for advanced forms, has made the molecular mechanisms underlying this neoplasia more and more intensively studied, with the intention of achieving a better understanding and advancing the treatment of this pathology.

  • squamous cell carcinoma
  • skin cancer
  • cancer stem cells
  • epigenetics

1. Mechanisms of SCC Carcinogenesis: Molecular Pathogenesis of SCC

Most SCCs do not arise as de novo tumors, but in an incremental manner from premalignant or noninvasive precursor lesions [1].
Actinic keratosis (AK) represents in a clinical fashion the first detectable precursor lesion of cSCC. Most AKs can either remain in the premalignant status or even regress spontaneously [2]. A small subset of AKs acquire additional genetic and epigenetic changes and progress to cutaneous squamous cell carcinoma in situ (SCCIS) and furthermore to cSCC. The risk of evolution from AK to SCC is very difficult to predict, with the numbers varying vastly between different studies (0.025–20%) [3]. Out of the cSCCs, only a small percentage can acquire additional genetic and epigenetic features that lead to metastatic disease [4].
Ultraviolet (UV) exposure is considered a risk factor that initiates the mutagenic process in the skin, leading to modified keratinocytes that have a survival advantage over unmutated keratinocytes; this then leads to the risk of selection of mutated keratinocytes over time. These mutated clones can acquire further genetic or epigenetic changes, leading to AKs, and further to SCCISs and cSCCs.
The development of cSCC is a multistep process requiring the accumulation of multiple genetic and epigenetic alterations in keratinocytes. These alterations lead to an augmented mutation rate by increasing cellular proliferation and reducing cell death in mutated keratinocyte population. DNA mutations are caused by either exogenous factors, such as UV radiation, chemicals, and ionizing radiation, or endogenous factors, such as reactive oxygen species (ROS), genome editing, mitotic errors, or errors in DNA repair [5][6].
Cumulative lifetime exposure to UV radiation is considered to be the most important carcinogen responsible for cSCC [7]. UV exposure over-activates the DNA repair systems of keratinocytes, leading to ATP consumption [8]. UVB radiation can produce DNA damage through structural rearrangements due to its high photonic energy. In case of a lack of repair of the damaged DNA strand before replication, the complementary strand will integrate the change in its base, leading to a constituted mutation [9]. This process leads to high rates of C > T transitions and CC > TT double base changes, thus generating a “UVB signature” [10][11]. Multiple genes have been postulated to be involved in the development of AKs and SCCs, with several molecular pathways and mechanisms being involved (Table 1).
Table 1. Mutated genes involved in the development of AKs and SCCs.
Gene Role
TP53
  • The most involved mutated gene in all types of cancers, but also in SCCs [12].
  • TP53 gene encodes p53 protein which plays a vital role in cell cycle.
  • Even though mutations in TP53 gene appears early in the evolution of SCCs, they cannot represent the sole mutation needed for cancerous progression [13].
NOTCH
  • Loss of function of NOTCH gene represents a premature sign of the conversion of healthy keratinocytes to their precancerous version [6][14].
  • Mutation of NOTCH genes has been found in both SCCs and dermoscopy-free dysplastic lesions that has been chronically exposed to sun, thus suggesting that NOTCH mutation can be considered a trademark for UV-damaged keratinocytes [15][16].
RAS
  • RAS mutation is characteristic for cSCCs developed in patients treated with Vemurafenib, a B-Raf inhibitor [17].
  • It is a rare spontaneous mutation in cSCCs [14][18].
CDKN2A
  • It encodes p16INK4a and p14ARF, which have the role of tumor-suppressor proteins [19].
  • p16INK4a inhibits cyclin D-dependent kinases in a direct manner, leading to the activation of retinoblastoma protein (RB) [20].
  • p14ARF isolates Mdm2 inside the nucleolus, preventing its interaction with p53 [21][22].
  • Mutation of CDKN2A plays an important role in both the appearance of AKs and the evolution of AKs to SCC [23]
PIK3CA
  • PIK3CA mutations were found in almost half of the cohort in a study, including AKs and SCCs, while in another cohort involving head and neck SCCs, ⅓ was found [18].
  • Tirbanibulin 1% ointment is used in the topical treatment of AKs with good efficacy, being based on a Src kinase inhibitor that acts on inhibiting PI3K (phosphatidylinositol 3-kinase) [24].
KNSTRN
  • It is considered to be part of the “UVB signature” [11].
  • It encodes a kinetochore protein that leads to the disruption of chromatin cohesion and, thus, aneuploidy and tumorigenesis [18].
FAT1
  • It encodes a protocadherin that can lead either to aberrant Wnt/β-catenin signaling or to increased CDK6 expression [25].
CARD11
  • CARD11 gene encodes a protein that scaffolds the role of nuclear factor kappa B (NF-kB) [26].
  • CARD11 mutations are found in UV-exposed skin and in the skin surrounding cSCC, and they have a role in the progression from normal to cancerous keratinocytes [27].
SRCASM
  • It encodes a tumor suppressor molecule with a VHS site, a GAT site, and multiple tyrosine phosphorylation domains [28].
  • Src-family tyrosine kinase (SFK) phosphorylation of the above molecule leads to limitation of keratinocyte proliferation and engagement in keratinocyte differentiation [28].
  • Both SCCISs and SCCs are associated with reduced SRCASM levels and a raised activity of SFKs [29][30].
TP63
  • TP63 gene encodes p63 protein, which is commonly found to be overexpressed in cSCCs [31].
EGFR
  • EGFR is found to be dysregulated in the development of cSCCs [32].
  • EGFR is involved in keratinocyte proliferation and differentiation and also influences the rate of survival of these cells [33].

2. Epigenetic Aspects of SCC: The Role of Epigenetics in Diagnosis, Metastatic Profile, and Prognosis

In recent years, special attention has been given to epigenetics and its involvement in the occurrence of chronic diseases in general, and cancers in particular [34]. Epigenetic changes include all the mechanisms through which changes occur in the expression of some genes, without interfering with the sequence of the nitrogenous bases that makes up the respective genes [35]. These are a result of the interactions between an organism and its environment, being represented by DNA methylation; histone modifications that influence the reading of certain DNA sequences; and miRNA-induced modifications, which can be transmitted from one cell to another within the same organism and even trans-generationally [36][37].
In general, the DNA of tumor cells is epigenetically characterized by global hypomethylation, with areas of hypermethylation at the level of 5’ cytosine-phosphate-guanine-3’ (CpG) islands, which are generally located in the promoter regions of some key genes. The above changes lead to genomic instability, activation of oncogenes, alteration of promoters of tumor suppressor genes, as well as damage to numerous essential cellular pathways involved in DNA repair, apoptosis, cell growth, angiogenesis, etc. [38][39][40].
In skin cancers, the involvement of epigenetics in the pathophysiology and characterization of melanoma is already recognized. These epigenetic mechanisms are considered as representing some of the earliest events in the initiation of oncogenesis [41]. However, the role of the interactions between the genome and the environment in the appearance and development of SCC, the second most common skin cancer, is less studied. The epigenetic profile seems to represent an important tool for characterizing the aggressiveness and metastatic potential of this type of skin cancer [42]. Moreover, multiple changes, such as CpG hypermethylation, seem to be involved in its occurrence [43]. The hypermethylation of certain CpG areas (induced especially by the effect of ultraviolet radiation, -thereby increasing the expression of dimethyltransferase 1) leads to changes in some proteins with an important role in keratinocyte homeostasis, which is associated with aggressive behavior and metastasis [44] (Table 2). Regarding post-translational modifications at the level of histones (through the processes of phosphorylation, acetylation, sumoylation, ubiquitylation, ribosylation of DNA, and glycosylation), these changes influence the way in which DNA sequences are exposed to reading, so that the transcription of some genes involved in keratinocyte differentiation is altered [45].
Besides DNA methylation, microRNA (miRNA) gene regulation is also present in the evolution of cSCC. Two types of miRNA are identified: those involved in the oncogenic process (which are involved in increasing cells’ proliferation and invasion capacity, the migration of keratinocytes, the formation of new cell colonies, and the loss of apoptotic capacity), and those with tumor suppressor capacity (which act by opposite mechanisms). MiR-203 is one of the most important tumor suppressor microRNAs involved in the pathogenesis of cSCC (being expressed in high levels in the skin), acting by modulating the expression of the oncogene c-MYC (suppressing its activity) and inhibiting the angiogenesis and cell cycle of tumoral cells. Additionally, a decrease in MiR-203 is associated with a low degree of cSCC differentiation and a worse prognosis [46]. Lohcharoenkal et al. have highlighted that MiR-130a also has tumor suppressor activity in cSCC by altering the bone morphogenetic protein (BMP)/SMAD pathway involved in tumor growth and invasion capacity. Thus, lower levels of MiR-130a have been found in cSCC samples compared to precancerous lesions or healthy skin [47]. Another miRNA that plays an important role in suppressing the proliferation and invasion of tumoral cells is miR-27; the downregulation of this MiRNA is associated not only with UVB radiation of the skin, but also with cSCC development [48]. MiRNAs 34a, 125b, 181a, 148a, 20a, 204, 199a, 124, and 214 are some of the investigated tumor suppressor MiRNAs involved in tumor progression, cell proliferation and differentiation, angiogenesis, and cell migration by targeting the expression of essential genes involved in these pathways [49]. Thus, lower expressions of these MiRNAs are observed in cSCC compared with normal skin.
On the contrary, numerous MiRNAs has been identified to promote tumoral cell initiation and progression, acting as protooncogenes. MiR-221 is a microRNA involved in numerous cancers (gastric cancer, ovarian cancer, breast cancer, etc.), with recent studies showing an upregulation of this small RNA fragment in cSCC by suppressing phosphatase and tenesin homolog (PTEN) gene, a tumor suppressor gene [50]. Yin et al. identified another microRNA involved in cSCC, highlighting that MiR-21 is upregulated in cSCC tissues by being involved in the invasion and metastasis of cSCC and by decreasing the activity of (tissue inhibitor of matrix metalloproteinase 3) TIMP3 gene. This gene is essential in modulating the activity of matrix metalloproteinases and molecules involved in angiogenesis, cell growth, and metastasis [50][51]. MiR-186 influences the aggressive character of cSCC, with its upregulation determining the inhibition of apoptotic protease-activating factor 1 (APAF 1) [52]. Additionally, some MiRNAs can be identified as prognosis factors. For example, a study conducted by Canueto et al. associated the presence of MiR-205 with a poor prognosis, being expressed in tumors characterized by histological risk factors, such as desmoplasia, nerve invasion, or an infiltrative character [53]. MiR 365, 31, 142, and 135b were also found to be involved in the regulation of genes responsible for cell invasion, migration, resistance to apoptosis, and proliferation [49]. Upregulation of MiR-664, 504, and 217 found in primary tumors seems to be associated also with the presence of an invasive behavior and a higher risk for metastatic disease. Gilespie et al. identified a group of miRNAs that are upregulated in tumors that metastasize compared to the primary one (miR-4286, miR-200a-3p, and miR-148-3p) and another group with aberrant expression in tumors with a high potential to metastasize (MiR-4286, MiR-421, MiR-4516, MiR-574-5p, MiR-135b, MiR-21, MiR-145, MiR-100, and MiR-214). Thus, these groups may be used in the future as markers of poor prognosis [54][55].
Regarding the role of histone changes in cSCC initiation and progression, the literature data are poor in identifying specific histone methylation and acetylation changes in sCC, even though their role in other cancers is well known. In cSCC, Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) (involved in histone methylation) seems to play a role in inhibiting the antitumoral immune response of the host, and it can be used in the future as an important target of specific antitumoral therapy [56].
Table 2. DNA methylation changes associated with cSCC.
Epigenetic Changes Involved Gene Involved Protein Role of the Protein Results
DNA methylation of CpG, leading to loss of function CDH1 gene promoter (E-cadherin gene promoter) E-cadherin Intercellular adhesion molecule Hypermethylation of this gene is more frequent in invasive forms of SCC compared to AK and normal population.
Hypermethylation of CDH1 gene promoter is present in 95% of cutaneous squamous cell carcinoma samples [57][58].
DNA methylation of CpG, leading to loss of function CDH13 gene promoter (T-cadherin gene promoter) T-cadherin Cell migration;
Phenotypic changes;
Calcium ion transport		 Hypermethylation of T-cadherin gene promoter is associated with phenotypic cellular changes, both in SCC and in actinic keratoses that will evolve into invasive SCC [59][60].
DNA methylation of CpG, leading to loss of function CDKN2A gene p16 (ARF) Tumor suppressor genes—cell cycle regulator proteins Hypermethylation is associated with a statistically significant decrease in the synthesis of aforementioned proteins (identified by immunohistochemical studies) (p < 0.001), with the inactivation of p16 and p14 [58].
DNA methylation of CpG, leading to loss of function CDKN2A gene p14 (INK4A)
DNA methylation of CpG, leading to loss of function Retinoblastoma protein 1 (RB1) gene RB1
DNA methylation of CpG, leading to loss of function SFRP1-5 promoter gene SFRP1-5 glycoproteins Modulatory effects on Wnt pathway Hypermethylation of the promoter region of these genes leads to a decrease in the expression of SFRP1-5 proteins in cSCC. It can be used as a marker of cSCC [61].
DNA methylation of CpG, leading to loss of function FRZB (frizzled-related protein) promoter gene FRZB protein Modulatory effects on Wnt pathway—involved in cell growth and differentiation Hypermethylation of the promoter of this gene is significantly higher in metastatic cSCC compared to non-metastatic forms (p = 0.00004). It can be used as a marker of subtypes with aggressive evolution [62].
DNA methylation of CpG, leading to loss of function Death-associated protein kinase 1 (DAPK1) gene DAPK1 Tumor suppressor activity—protein involved in apoptosis and autophagy DAPK1 hypermethylation is much more frequent in invasive forms of cSCC [60].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24076646

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