**Non-melanoma Skin Cancers**

[85] Mukherjee N, Reuland SN, Lu Y, Luo Y, Lambert K, et al. Combining a BCL2 inhibitor with the retinoid derivative Fenretinide targets melanoma cells including melanoma ini-

[86] Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nature

[87] Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, et al. A landscape of driver

[88] Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, et al. Beyond BRAF(V600): Clinical mutation panel testing by next-generation sequencing in advanced melanoma.

tiating cells. The Journal of Investigative Dermatology. 2015;**135**(3):842-850

Medicine. 2013;**19**(2):202-208

132 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

mutations in melanoma. Cell. 2012;**150**(2):251-263

The Journal of Investigative Dermatology. 2015;**135**(2):508-515

**Chapter 6**

**Provisional chapter**

**Squamous Cell Carcinoma: Biomarkers and Potential**

Squamous cell carcinoma (SCC) is the second most frequent non-melanoma skin cancer (NMSC) and carries with it a significant psychosocial and economic burden for both patients and health-care systems. Known risk factors for SCC include chronic ultraviolet (UV) exposure, chronic wounds and inflammation, exposure to certain chemicals and immunosuppression. The considerable risk of SCC recurrence and metastasis has driven the need for the discovery of new molecules that could explain the initiation and biological behavior of this type of NMSC. In this respect, proteomic research techniques have rapidly evolved and adapted in order to connect missing links and single out distinctive skin cancer biosignatures. Proteomic analysis of normal, dysplastic, and malignant keratinocytes appears to be promising in respect to SCC biomarker discovery, with the potential to aid in risk assessment, early detection, disease progression and development of novel targeted therapeutic agents. Identifying changes in the keratinocyte proteome pattern from normal to inflammatory and malignant cells will lead to the discovery of novel SCC biomarkers that could represent valuable tools for patient screening, diagnosis, management and follow-up. **Keywords:** squamous cell carcinoma, keratinocytes, carcinogenesis, biomarkers, proteomics,

**Squamous Cell Carcinoma: Biomarkers and Potential** 

DOI: 10.5772/intechopen.70767

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Squamous cell carcinoma (SCC) accounts for about 25% of non-melanoma skin cancers (NMSC) and together with basal cell carcinoma (BCC) (75%), it represents the most frequent

**Therapeutic Targets**

**Therapeutic Targets**

Monica Neagu

**Abstract**

diagnosis, therapy

**1. Introduction**

Monica Neagu

Vlad-Mihai Voiculescu, Constantin Caruntu, Iulia Solomon, Mihai Lupu, Mihaela Adriana Ilie,

Vlad-Mihai Voiculescu, Constantin Caruntu, Iulia Solomon, Mihai Lupu, Mihaela Adriana Ilie,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Daniel Boda, Carolina Constantin and

Daniel Boda, Carolina Constantin and

http://dx.doi.org/10.5772/intechopen.70767

**Provisional chapter**

## **Squamous Cell Carcinoma: Biomarkers and Potential Therapeutic Targets Therapeutic Targets**

**Squamous Cell Carcinoma: Biomarkers and Potential** 

DOI: 10.5772/intechopen.70767

Vlad-Mihai Voiculescu, Constantin Caruntu,

Vlad-Mihai Voiculescu, Constantin Caruntu, Iulia Solomon, Mihai Lupu, Mihaela Adriana Ilie, Daniel Boda, Carolina Constantin and Monica Neagu Iulia Solomon, Mihai Lupu, Mihaela Adriana Ilie, Daniel Boda, Carolina Constantin and Monica Neagu Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70767

#### **Abstract**

Squamous cell carcinoma (SCC) is the second most frequent non-melanoma skin cancer (NMSC) and carries with it a significant psychosocial and economic burden for both patients and health-care systems. Known risk factors for SCC include chronic ultraviolet (UV) exposure, chronic wounds and inflammation, exposure to certain chemicals and immunosuppression. The considerable risk of SCC recurrence and metastasis has driven the need for the discovery of new molecules that could explain the initiation and biological behavior of this type of NMSC. In this respect, proteomic research techniques have rapidly evolved and adapted in order to connect missing links and single out distinctive skin cancer biosignatures. Proteomic analysis of normal, dysplastic, and malignant keratinocytes appears to be promising in respect to SCC biomarker discovery, with the potential to aid in risk assessment, early detection, disease progression and development of novel targeted therapeutic agents. Identifying changes in the keratinocyte proteome pattern from normal to inflammatory and malignant cells will lead to the discovery of novel SCC biomarkers that could represent valuable tools for patient screening, diagnosis, management and follow-up.

**Keywords:** squamous cell carcinoma, keratinocytes, carcinogenesis, biomarkers, proteomics, diagnosis, therapy

#### **1. Introduction**

Squamous cell carcinoma (SCC) accounts for about 25% of non-melanoma skin cancers (NMSC) and together with basal cell carcinoma (BCC) (75%), it represents the most frequent

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

skin malignancy worldwide [1, 2]. Particularly, in the last several decades, the risk of developing cutaneous squamous cell carcinoma (cSCC) has been increasing epidemically, reaching approximately 7–11% [3]. Clinically, cSCC shows up red patches, rough or scaly, that can bleed or crust with slow healing. The affected skin is usually the one that is most exposed to sunlight, and body regions such as the head, face, neck and dorsum of the hands can carry a significant risk of developing cSCC. Seldom, it occurs in genital areas. However, it is important to know that cSCC can also be found in scars or skin sores [4]. Although numerous risk factors for developing cSCC have been noted, one of the most significant etiological factors is ultraviolet (UV) light that is responsible for damaging DNA, followed by chemicals, ionizing agents, radiation, chronic skin ulceration, weakened immune system, HPV infection, smoking, light-colored skin, and male gender [4]. In almost 65% of cases, cSCC arises from premalignant conditions such as actinic keratosis [5]. Also, immunosuppression caused by organ transplant or chemotherapy targeting BRAF favors the development of cSCCs with RAS mutations, elevating steadily the incidence of skin cancer by over 65-fold [6].

(290–320 nm), this range has an increased mutagenic and carcinogenic potential by comparison with UVA (320–400 nm), being the most harmful constituent of sunlight that reaches the Earth surface [14]. Chronic and excessive exposure to UV radiation conveys many health risks where, besides photoaging, genomic and proteomic alterations at skin level can lead to immunosuppression favorable to the most common forms of skin cancer, BCC, SCC and melanoma. Genetic factors such as polymorphisms of the melanocortin 1 receptor gene can also influence

Squamous Cell Carcinoma: Biomarkers and Potential Therapeutic Targets

http://dx.doi.org/10.5772/intechopen.70767

137

The UV-derived effects on skin cells in the proteomic context have not commonly been approached in photobiology and, as a consequence, only a few studies could be retrieved in this domain [16]. Although UVA is about 20-times more abundant than UVB in incident sunlight, its damaging potential on cellular DNA is less dangerous than UVB. The UVA effects are mediated by reactive oxygen species (ROS) that induce oxidative stress affecting the pro-

Almost entirely, published studies refer to UVB effects as triggers of significant alterations in skin cell layers, especially in keratinocytes, the major cell type of the epidermis and the main defensive barrier against external threats. UVB could also raise the increased ROS level responsible for oxidative damage of nucleic acids and proteins. Normal human epithelial keratinocytes isolated from foreskin and subjected to UVB were tested by parallel proteomics approach for assessing the protein expression profile and also for identifying proteins modified through chemical oxidation. In UVB-irradiated keratinocytes, various proteins involved in cellular homeostasis such as cytoskeleton integrity, removal of damaged proteins or heat shock response were differentially regulated (e.g., prohibitin, integrin alpha-3, cytokeratin 5, proteasome subunit alpha type-6) while some specific proteins with roles in cell adhesion, intercellular interaction, and protein folding were carbonylated (e.g., Glucosidase 2 b subunit, GRP 78, actin-related protein 3, annexin 2). These protein alterations driven by UVB exposure could cause cell homeostasis deregulation and eventually

Although it was reported that keratinocytes are more resistant to UV than other cell types, recurrent exposures to UVB induce at keratinocyte level, a so-called alternative state of differentiation, noticeable even 64 h after exposure [19]. Thus, a 2D-DIGE proteomic profiling of this specific state revealed a 69 differentially abundant protein patterns belonging to differentiation and survival keratinocyte machinery. Specifically, upon UVB action, an increased expression of a protein called TRI partite Motif Protein 29 (TRIM29) was noticed, further confirmed by Western blot assay. TRIM29 protein protects against UVB exposure damaging effects, as knocking down the TRIM29 expression by RNA interference, the viability of keratinocytes declined. These findings suggest that TRIM29 protein contributes to the survival of differentiating keratinocytes by inducing an alternative differentiation status protecting cells from dying, owing to UVB exposure-related stress [20]. The enhanced expression of TRIM29 as keratinocytes "regenerator" should be associated *in vivo* with the altered expression of other key proteins (heat shock proteins, cytokeratin, and cytoskeletal proteins), inflammation process, epidermis remodeling, and immune response type, as these could be novel mecha-

teome through oxidation of DNA repair proteins, thus inhibiting DNA repair [17].

the skin's sensitivity to UV and enhance cancer risk [15].

trigger cellular senescence or carcinogenesis [18].

nisms of keratinocyte survival upon UV damage [16, 21].

Even though its mortality rate is relatively low, approximately 2.1%, cSCC has many subtypes that widely vary from harmless to aggressive skin tumors with important metastatic potential, from 2 to 10% [7]. Initially, it invades adjacent tissue, then the regional lymph nodes and ultimately it affects distant organs [8]. The localization of cSCC influences the risk of recurrence and dissemination; cSCC affecting the lips or ears was demonstrated to have a higher risk of invasion (10–25%) [9]. In addition, an up-to-date prospective study established that a primary skin tumor size above 2 cm has a 15% chance of recurrence and a 30% chance of metastasis. Also, histological features such as speed of tumor growth, tumor depth greater than 4 mm, poor differentiation, perineural and subcutaneous invasion is associated with aggressive cSCC, leading to significant morbidity and mortality [8, 10, 11].

Although the vast majority of cSCC usually respond well to conventional treatments including wide surgical excision, chemotherapy, targeted therapy and radiotherapy, none of them can ensure the cure. Hence, approximately 3–5% of cSCCs recur and almost 5% metastasize within 5 years [8]. In addition, approximately 5% of metastatic cSCCs are associated with very poor clinical outcomes. There are no therapies officially approved by the FDA with a specific indication for metastatic cSCC and so the development of new agents has been relatively deliberate, due to a limited knowledge of the molecular basis of this disease. Therefore, there is a high necessity of identifying the complete genomic portrait of cSCC represented by multiple genes with recurrent mutation, amplificatiotn, and deletion including several other alterations which are aimed at developing new biomarker-associated therapeutic targets [12].
