~ Pathogenesis ~

Learning Outcomes

Explain how UV radiation acts as a complete carcinogen
Describe the role of p53 as the guardian of the genome.
Outline the genetic and molecular pathways underlying BCC and SCC
Identify the key oncogenic mutations driving melanoma progression and how skin tumors evade immune destruction
Explain the carcinogenic mechanisms of arsenic and co-factors
Assess the relationship between the endocannabinoid system and skin cancer

Overview

Skin carcinogenesis is a complex process involving genetic, molecular, and environmental factors, and this is particularly evident in the development of basal cell carcinoma, squamous cell carcinoma, melanoma and the precursor lesion actinic keratosis.¹

Ultraviolet (UV) Radiation: The Complete Carcinogen

Ultraviolet radiation affects every stage of carcinogenesis through a range of distinct but interconnected mechanisms. UVB radiation is directly absorbed by DNA, causing UV-signature mutations, with the earliest event being keratinocyte apoptosis controlled by the p53/p21/bax/bcl-2 pathway.² UVA radiation, by contrast, produces reactive oxygen species and free radicals that cause oxidative damage to DNA, and additionally induces nitric oxide synthase to form peroxynitrate, a compound highly toxic to DNA, rather than the usual nitric oxide.²

Beyond direct DNA damage, ultraviolet radiation also exerts significant immunosuppressive effects. It disrupts the dendritic network of Langerhans cells, thereby reducing cell-mediated immune responses, and drives the activation of regulatory T cells that produce immunosuppressive cytokines such as IL-10 and IL-4.²

Chronic UVB radiation further contributes to carcinogenesis by activating heparanase, an enzyme that cleaves heparan sulfate proteoglycans in the extracellular matrix. This cleavage releases growth factors and promotes angiogenesis, cell proliferation, and inflammation, collectively creating a microenvironment that is conducive to tumour development.²

General Mechanisms of UV Damage

UV light induces DNA breaks and mutations in keratinocytes, and directly mutates the p53 gene, disabling the safety checks that would normally either repair DNA breaks or initiate the formation of sunburn cells, which are apoptotic cells arising in response to DNA damage.² As a result of this impaired surveillance, DNA-damaged cells are able to survive and ultimately transform into malignancy.

UV light also suppresses local immune responses through several mechanisms.² It upregulates RANK ligands in keratinocytes and induces the proliferation of regulatory T cells, collectively suppressing the body's physiological immune surveillance in the skin.² This is further compounded by the downregulation of FAS-ligand, a key surveillance molecule in the basal layer that ordinarily functions to eliminate sunburn cells, the loss of which allows damaged cells to persist and progress toward malignant transformation.²

Arsenic and UV Radiation

Arsenic acts as a co-carcinogen in skin cancer development.³ When combined with UV radiation, it shortens the time required for tumour induction, increases the total number of tumours, and leads to a higher percentage of invasive squamous cell carcinomas.³ The primary mechanism by which arsenic exerts this effect is through inhibition of the normal apoptosis that UV-damaged cells would otherwise undergo, thereby allowing these cells to survive and progress toward malignancy.³

Skin carcinogenesis is therefore driven by a combination of environmental triggers, of which UV radiation is the predominant factor, acting alongside co-carcinogens such as arsenic. Central to this process is the failure of apoptosis, the mechanism that would ordinarily eliminate damaged cells and prevent their malignant transformation.

P53 Tumor Suppressor Gene

p53 is known as the guardian of the genome, coordinating DNA repair, cell cycle arrest, and apoptosis in order to prevent the survival of damaged cells.² UV radiation directly mutates the p53 gene, disabling the cell's ability to repair DNA or undergo programmed cell death.² This loss of function leads to the clonal expansion of initiated cells into pre-malignant and eventually malignant lesions.

1. UV-Induced "Signature" Mutations

UVB and UVC cause specific types of DNA damage that result in unique signature mutations in p53 Cyclobutane-type pyrimidine dimers: C to T and CC to TT transitions at dipyrimidine sites (detected in 50% across all human cancers, and nearly all skin carcinomas). ²

2. Failure of Protective Mechanisms

In a healthy cell, p53 protein levels rise in response to UV damage, triggering G1 cell cycle arrest and allowing time for DNA repair to occur before mitosis.² If the damage is too extensive to be repaired, p53 will instead initiate apoptosis to eliminate the damaged cells, as seen in the formation of sunburn cells.² When p53 is mutated, however, these protective mechanisms fail, and cells carrying damaged DNA are able to survive and proliferate rather than being eliminated.

3. Early Initiation and Clonal Expansion

p53 mutation is an early event in skin carcinogenesis, distinguishing it from the majority of other cancers where p53 mutations tend to occur later in disease progression.² These mutations are found at high frequencies in normal-appearing sun-exposed skin and in actinic keratosis, which is a precursor lesion to squamous cell carcinoma.² UV radiation acts as a tumour promoter by driving the clonal expansion of these mutated cells, as p53 mutant keratinocytes are resistant to UV-induced apoptosis and are therefore able to survive while the surrounding normal cells die.² Over time, these mutant clones colonise and repopulate the epidermal stem cell compartments, establishing a foundation for further malignant progression.

4. Role of Downstream and Related Molecules

p53 influences several downstream molecules and pathways that further contribute to cancer development. Through the Fas/Fas-ligand pathway, chronic UV exposure leads to loss of FasL expression, and when combined with p53 mutations, mutated cells are able to evade immune-mediated apoptosis.² This is particularly significant given that the Fas/Fas-ligand pathway is normally vital for maintaining immune homeostasis, eliminating infected or tumour cells, and establishing immune privilege in specialised areas such as the eye and testis.

With respect to cell cycle regulation, mutated p53 fails to properly activate key downstream targets. P21, which is necessary for G1 arrest, and MDM2, which ordinarily regulates p53 levels, are both disrupted as a consequence. MDM2 also functions as an oncogene, and in the context of cancer it becomes uncontrolled and acts to completely destroy p53, further undermining genomic stability.²

P63 and p73 are p53-related genes that perform tumour suppressor functions in epithelial tissues.² When these genes are lost, the result is the development of aggressive tumours, underscoring the broader importance of the p53 family in maintaining epithelial integrity and preventing malignant transformation.

5. Pathogenesis in High-Risk Groups

The pathogenesis of skin cancer is accelerated in certain populations with underlying genetic or immunological vulnerabilities. Li-Fraumeni syndrome is a rare, inherited autosomal dominant disorder caused by mutations in the TP53 tumour suppressor gene, in which affected individuals inherit a mutated p53 allele.² This significantly increases the risk of developing multiple early-onset cancers, including sarcomas, breast cancer, brain tumours, and adrenocortical carcinoma.

Xeroderma Pigmentosum is another rare inherited genetic disorder characterised by extreme sensitivity to UV radiation and an inability to repair sun-damaged DNA due to a defective DNA repair mechanism. This results in a more than 1,000-fold increased risk of basal cell carcinoma and squamous cell carcinoma formation.²,⁴

Immunosuppression also plays an important role in accelerating this process. Recipients of organ transplants show high incidences of p53 mutations and protein accumulation in their skin tumours, suggesting that a lack of immune surveillance further enables the progression of p53-mutated cells toward malignancy.²,⁴

Sonic Hedgehog (SHH) Pathway (BCC)

The most critical genetic alteration in BCC involves the SHH signaling pathway, specifically the inactivation of the Ptch1 gene. Over-activation of Gli1 and Gli2 transcription factors and the FOXM1 protein, which drive tumoral cell hyperproliferation.⁵

The AK-SCC Continuum

Squamous cell carcinoma is thought to arise from actinic keratosis through a multistep process of gradually acquired mutations.⁵ The classic pathway describes a stepwise evolution beginning with atypia confined to the lowest third of the epidermis in actinic keratosis grade I, progressing to involvement of the middle third in grade II, and finally extending to the upper third of the epidermis in grade III, before advancing to invasive disease.⁵

An alternative route is the differentiated pathway, whereby invasive squamous cell carcinoma develops directly from the atypical basal layer of an actinic keratosis grade I lesion.⁵ In this pathway, atypical cells directly invade the dermis, often via hair follicles, bypassing the traditional progression through the thicker grade II and grade III lesions. This makes early-stage, thin actinic keratoses a significant source of high-risk invasive squamous cell carcinoma, and highlights the differentiated pathway as a prominent mechanism in the development of invasive disease.⁵

Mitochondrial DNA (mtDNA) Deletions

The mtDNA4977 deletion has been identified as a significant indicator of non-melanoma skin cancer risk, appearing at levels three times higher in sun-exposed skin compared to non-exposed skin.⁵

Pathogenesis of Melanoma

Mutations in the NRAS and BRAF genes activate the ERK-MAPK pathway, leading to uncontrolled melanoma cell growth.⁴ Loss mutations in CDKN2A and PTEN further promote cell survival through distinct mechanisms.⁴ Inactivated CDKN2A prevents the recruitment of the ARF protein, which would ordinarily arrest the cell cycle and promote cell death following DNA damage via p53 accumulation. Loss of PTEN leads to rising levels of PIP3 and AKT, which inactivates the Bcl-2 antagonist BAD, thereby prolonging the survival of damaged cells.

AKT activation also stimulates MITF, the microphthalmia-associated transcription factor, which functions as an oncogene and master regulator of melanocyte development. MITF is a critical lineage-specific oncogene in melanoma, driving cell survival, proliferation, and differentiation.⁴

Additionally, alterations in cadherins and integrins contribute to disease progression, with increased expression of αVβ3 integrin facilitating cell adhesion and signalling pathways that promote tumour growth, metastasis, and therapy resistance.⁴

Mechanisms of Immune Evasion

Established skin tumours develop sophisticated mechanisms to evade immune destruction. One such mechanism involves the re-expression of FasL on the tumour cell surface, which allows cancer cells to counter-attack the immune system by inducing apoptosis in attacking immune effector cells that express the Fas receptor.⁴ Tumours also acquire resistance to both extrinsic and intrinsic apoptotic pathways, achieved through the manipulation of caspases and the overexpression of inhibitors such as cFLIP, collectively enabling malignant cells to persist in the face of immune-mediated destruction⁴

Skin tumours further evade immune destruction through the downregulation of HLA-I proteins, which prevents CD8+ T lymphocytes from recognising tumour antigens.⁴ Complementing this, abnormal expression of HLA-G protein delivers inhibitory signals to both Natural Killer cells and T cells, protecting the tumour from destruction.⁴

In squamous cell carcinoma specifically, high expression of complement factor H allows malignant cells to evade complement-mediated destruction.⁴ Additionally, overexpression of the protein Serpin A9 has been associated with increased tumour invasiveness.⁴

Arsenic Exposure (Arsenicosis)

Arsenic exposure, or arsenicosis, leads to skin cancer through the interplay of oxidative stress, genotoxicity, immune dysfunction, and disrupted signal transduction.

Oxidative and Nitrosative Stress

Arsenic creates a pro-tumorigenic environment primarily through the generation of reactive oxygen species and reactive nitrogen species.³ Arsenic-induced DNA damage leads to mitochondrial damage, and increases the expression and activity of NADPH oxidase, which produces superoxide.³ This superoxide promotes cancer growth, survival, and metastasis by inducing further DNA damage and altering cell signalling.

Arsenic also reduces the availability of the protective molecule nitric oxide by binding to and inhibiting nitric oxide synthase through enzyme uncoupling, resulting in the production of superoxide rather than nitric oxide.³ Furthermore, arsenic targets and depletes natural antioxidants such as glutathione, which is essential for maintaining redox homeostasis, thereby further compromising the cell's capacity to neutralise oxidative damage.³

Immune Dysfunction and ER Stress

Arsenic causes ubiquitous damage to the genome and destabilises it through multiple mechanisms.³ It induces chromosomal aberrations and sister chromatid exchanges, and hampers numerous DNA repair mechanisms by inhibiting DNA polymerase beta, PARP, and ERCC2 protein, thereby disrupting nucleotide excision repair, base excision repair, and mismatch repair.³

Arsenic also modulates DNA methylation by depleting S-adenosylmethionine, the primary pool of methyl group donors within the cell.³ This depletion leads to the hypermethylation and consequent silencing of tumour suppressor genes, including p16 and DAPK, further undermining the cell's defences against malignant transformation.³

Disrupted Signal Transduction

Arsenic orchestrates disease progression by activating oncogenes and upregulating inflammatory pathways through several mechanisms. Through activation of the Hippo signalling pathway and dysregulation of YAP, the yes-associated protein, arsenic promotes epithelial cell proliferation and survival.³ It also activates the MDIG oncogene and upregulates cyclin D1, driving cell cycle progression.³

Arsenic further stimulates the MAPK pathways, including ERK1/2, p38, and JNK, which normally regulate cancer cell proliferation, survival, apoptosis, and metastasis.³ While ERK1/2 typically promotes proliferation, p38 and JNK ordinarily act as stress-activated kinases capable of inducing apoptosis. The dysregulation of these pathways by arsenic therefore drives cancer growth by disrupting this balance.

Finally, arsenic activates NF-κB, promoting chronic inflammation and cell survival, and thereby creating a sustained pro-tumorigenic environment conducive to malignant progression.³

Additional Risk Factors and Molecular Markers

Ionizing Radiation (X-Rays)

Exposure to X-rays leads to double-stranded breaks in DNA.²,⁴ The accumulation of p53 and the phosphorylation of histone H2AX are key cellular responses to this damage, serving to coordinate repair and prevent malignant progression.²,⁴ However, when these mechanisms are inactivated, the cell loses its capacity to adequately respond to DNA damage, thereby permitting cancer growth.

Viral Co-Factors (HPV)

Beta-HPV is a known co-factor in squamous cell carcinoma pathogenesis, particularly in immunosuppressed patients, where it alters DNA repair mechanisms and immune surveillance.⁵ Alpha-HPV, such as HPV77, can produce E6 and E7 proteins that deregulate the p53 and Rb tumour suppressor pathways, further contributing to malignant transformation.⁵

The Endogenous Cannabinoid System (ECS)

The endocannabinoid system consists of specific G-protein coupled receptors, namely CB1 and CB2, their lipid ligands known as endocannabinoids, and the enzymes responsible for their synthesis and degradation. Despite its known role in downregulating inflammatory immune responses in other contexts, the endocannabinoid system does not appear to play a role in the pathogenesis of skin cancer.¹ This was investigated by observing the development of chemically induced skin tumours in both wild-type and CB1/CB2-receptor-deficient mice.¹ No significant difference was found in the development of fibrosarcomas following inoculation with 3-methylcholanthrene, nor in the incidence or number of papillomas per mouse using the DMBA-TPA model, nor in melanoma incidence or tumour count in melanoma-prone mice.¹ Taken together, these findings suggest that the endocannabinoid system does not meaningfully contribute to skin cancer pathogenesis.

Exogenous Cannabinoids (THC)

Systemically applied THC has been shown to significantly inhibit the growth of certain melanomas in a CB receptor-dependent manner, as the treatment was ineffective in CB1/CB2 receptor-deficient mice.¹ This effect is attributed to the antagonism of the pro-inflammatory tumour microenvironment. However, THC did not affect the proliferation of melanoma cell lines directly, which is explained by the low expression levels of CB1 and CB2 receptors on these cells.

THC treatment was found to reduce the infiltration of CD45+ immune cells into melanoma tissues, particularly myeloid-derived macrophages and neutrophils, which are recognised drivers of pro-tumorigenic growth.¹ Notably, THC did not affect the density of blood vessels within tumours, indicating that its inhibitory effects operate independently of angiogenesis.¹

Pathogenesis of Non-Melanoma Skin Cancer

The primary pathway for squamous cell carcinoma is the p53 mutation.⁵ As these mutations accumulate due to solar exposure, they facilitate the clonal expansion of affected keratinocytes, leading to the formation of premalignant actinic keratosis. Depending on the state of the immune system, these lesions can progress into invasive squamous cell carcinoma.

In basal cell carcinoma, while p53 mutations are present in approximately 56% of cases, a distinct additional mechanism involves the Hedgehog signalling pathway. Mutations in the patched or smoothened genes lead to the continuous overactivation of Gli transcription factors, and specifically the overexpression of Gli2, which serves as the primary transducer of Hedgehog signalling.⁵ This drives the upregulation of anti-apoptotic proteins such as Bcl-2 and cFLIP, creating marked resistance to cell death and thereby facilitating tumour development and progression.⁵

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Test Your Knowledge

1. Which type of UV radiation directly causes cyclobutane-type pyrimidine dimers and UV-signature mutations in DNA?

A) UVA

B) UVB

C) UVC

D) Both UVA and UVB

2. What is the primary mechanism by which arsenic acts as a co-carcinogen when combined with UV radiation?

A) Activating the Hedgehog signalling pathway

B) Increasing reactive oxygen species production

C) Inhibiting normal apoptosis of UV-damaged cells

D) Downregulating HLA-I proteins

3. Which of the following best describes the "differentiated pathway" in SCC development?

A) Progression from AK grade I → II → III → invasive SCC

B) Direct dermal invasion from atypical basal cells of AK grade I, often via hair follicles

C) Activation of Gli transcription factors leading to keratinocyte proliferation

D) p53 mutation driving clonal expansion through all epidermal layers

4. In melanoma pathogenesis, what is the downstream effect of PTEN loss?

A) Overactivation of the SHH pathway

B) Increased ARF protein activity arresting the cell cycle

C) Rising PIP3 and AKT levels, inactivating the pro-apoptotic protein BAD

D) Direct mutation of the BRAF gene

5. How do established skin tumours exploit the Fas/FasL pathway to evade immune destruction?

A) They downregulate FasL, preventing immune cell recognition

B) They re-express FasL on the tumour surface to induce apoptosis in attacking immune cells C) They upregulate caspases to resist Fas-mediated signals

D) They suppress RANK ligand expression in surrounding keratinocytes

6. What is the significance of the mtDNA4977 deletion in skin cancer?

A) It directly mutates the p53 gene in melanocytes

B) It is found at levels three times higher in sun-exposed skin and is a significant indicator of NMSC risk

C) It activates the ERK-MAPK pathway in melanoma cells

D) It causes chromosomal aberrations similar to arsenic exposure

7. Which of the following correctly describes how arsenic disrupts DNA methylation?

A) It hypomethylates and activates oncogenes like BRAF and NRAS

B) It depletes S-adenosylmethionine, leading to hypermethylation and silencing of tumour suppressor genes such as p16 and DAPK

C) It inhibits PARP and ERCC2, preventing base excision repair

D) It activates NF-κB, which directly methylates tumour suppressor promoters

8. What does experimental evidence suggest about the role of the endocannabinoid system (ECS) in skin cancer pathogenesis?

A) CB1 activation promotes melanoma growth via inflammatory signalling

B) The ECS plays a significant role in BCC development through Gli pathway modulation

C) The ECS does not meaningfully contribute to skin cancer pathogenesis, based on findings from CB1/CB2 receptor-deficient mouse models

D) CB2 receptors mediate immune evasion in squamous cell carcinoma

9. In basal cell carcinoma, what is the consequence of mutations in the patched or smoothened genes?

A) Loss of p53 function and failure of G1 cell cycle arrest

B) Continuous overactivation of Gli transcription factors, particularly Gli2, driving upregulation of anti-apoptotic proteins

C) Increased expression of αVβ3 integrin facilitating metastasis

D) Activation of heparanase and degradation of the extracellular matrix

10. Why are p53 mutations considered particularly significant in skin carcinogenesis compared to other cancers?

A) They are the rarest type of mutation found in skin tumours

B) They only occur in melanoma and not in NMSC

C) They occur late in disease progression, making early detection difficult

D) They occur early, are found in normal sun-exposed skin and actinic keratosis, and confer resistance to UV-induced apoptosis, enabling clonal expansion

Answer Key

References

Glodde N, Jakobs M, Bald T, Tüting T, Gaffal E. Differential Role of Cannabinoids in the Pathogenesis of Skin Cancer. Life Sciences. 2015 Oct;138:35–40.
BENJAMIN C, ANANTHASWAMY H. p53 and the Pathogenesis of Skin Cancer. Toxicology and Applied Pharmacology. 2007 Nov 1;224(3):241–8.
Hunt KM, Srivastava RK, Elmets CA, Athar M. The Mechanistic Basis of arsenicosis: Pathogenesis of Skin Cancer. Cancer Letters [Internet]. 2014 Nov;354(2):211–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193806/
Erb P, Ji J, Kump E, Mielgo A, Wernli M. Apoptosis and Pathogenesis of Melanoma and Nonmelanoma Skin Cancer. Sunlight, Vitamin D and Skin Cancer. 2008;624:283–95.
Didona D, Paolino G, Bottoni U, Cantisani C. Non Melanoma Skin Cancer Pathogenesis Overview. Biomedicines. 2018 Jan 2;6(1):6.

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