**10. Conclusions**

According to Shiraki et al. [100], cyclin D1 and EGFR together correlate to low survival rates of OSCC patients. It is worth mentioning that despite being an oncogenic gene with a major role to play in tumor invasion, cyclin D1 (independent of EGFR) bears no pathological signifi-

Recent years have seen a shift toward therapy and prognosis, with a strong emphasis on those molecular biomarkers associated with tumor suppression and apoptosis, especially p53/p63 and Bcl-2 [101]. High levels of Bcl-2 have been proven to correlate to low survival rates of

Another important factor in the carcinogenesis of human solid tumors is hypoxia; it is responsible for the adaptive modifications of malignant cells allowing them to survive [105, 106]. Unfortunately, little data is available to help scale its importance within the framework of OSCC prognosis. Antitumor therapy targeting angiogenic biomarkers has been a subject to many recent studies. This is due to the fact that angiogenic processes play a key role in the formation of neo-capillary networks and is essential to cancer growth, progression and metastasis [107]. Thus, the most important angiogenic biomarker involved in carcinogenesis and OSCC tumor dissemination is VEGF which plays a crucial role in the maintenance of tumor vascula-

Tumor invasion is based on several factors, including cellular interaction, requiring both matrix degradation enzymes (MMPs) and cell adhesion proteins (cadherins). MMP is a family of proteases expressed by invasive tumors and adjacent stroma. They were also associated with low survival rates in patients with OSCC without lymph node metastasis [110]. Cadherins are transmembrane glycoproteins with important functions in cell adhesion mak-

Vaginal squamous cell carcinoma (VaSCC) is a tumor with a relatively low occurrence rate of 1–2% of all gynecological malignancies [112], but it can occur in approximately 30% of cervical cancer cases [113, 114]. Despite the low number of studies concerning this type of cancer, epidemiological, virological and clinical-pathological data available show two distinct entities of this genital SCC. They develop through two etiopathogenic pathways: one is linked to HPV infection, while the second is HPV-independent. Available studies do not provide enough information on their significance to the final outcome and they require further investigation. However, it is known that most VaSCCs are closely related to HPV, emphasizing the

As far as the biomarkers linked to genital SCC [23, 115–117] are concerned, their discovery is relevant due to their significant impact on early diagnosis and timely treatment. Numerous studies link p16 expression with a less aggressive form of vulvar SCC and a reduced death rate. On the other hand, patients exhibiting p53 mutation have a worse prognosis, frequent relapses, and greater associated mortality [118]. Other molecular markers with a negative impact on SCC patients are cofilin-1, galectin-7, and wee1 [119]. Moreover, it has been found

ing them important in tumor invasion and metastasis [111].

idea that it shares a common pathway with cervical cancer [114].

**9. Biomarkers in genital SCC**

cance to OSCC.

ture [108, 109].

OSCC patients [102–104].

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

cSCC is associated with different trigger factors such as UV radiation, especially UVB which induces the alteration of skin layers and therefore the destruction of defensive barrier against external threats, but also the oxidative damage of nucleic acids and proteins through the increased levels of ROS. Therefore, an increased expression of TRIM29 is observed with the survival of differentiating keratinocytes. The chemical factors responsible for inducing SCC are also interfering in the keratinocyte differentiation and proliferation.

The exposure to UV radiation determine mutations of p53 tumor suppressor gene (responsible for apoptosis, cell proliferation, and DNA differentiation) together with the modifications of different biomarkers such as E-cadherin (a decrease in E cadherin expression in the primary lesion is correlated with the development of regional lymph node metastases), Ki-67 (associated with recurrent aggressive tumors) and cyclin D1 (a proto-oncogene which is essential in the development of skin cancer leading to the organization and abnormal differentiation of tissues). Furthermore, the expression of S100A7 which belongs to Ca2+-modulated proteins S100 family is associated with increased survival rate, while its poor expression correlates with significant cell differentiation.

Another important role in carcinogenesis is attributed to cancer stem cells which derive from the transformation of normal cell or through the differentiation of tumor cells migrating through normal tissue. CD 133 is one of the most important biomarkers linked to proliferation and differentiation of skin cancers so that new therapeutic targets are needed to be focused on this transmembrane hematopoietic stem cell glycoprotein.

**Acknowledgements**

**Author details**

**References**

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Education, Research, Development and Innovation.

Daniel Boda1,4, Carolina Constantin5,6 and Monica Neagu5,6,7

\*Address all correspondence to: costin.caruntu@gmail.com

2 "Elias" University Emergency Hospital, Bucharest, Romania

5 "Victor Babes" National Institute of Pathology, Bucharest, Romania

1 "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

Vlad-Mihai Voiculescu1,2, Constantin Caruntu<sup>1</sup>

3 MedAs Medical Center, Bucharest, Romania 4 Carol Medical Center, Bucharest, Romania

6 Colentina University Hospital, Bucharest, Romania 7 Faculty of Biology, University of Bucharest, Romania

This paper is partly supported by grants PNII-PT-PCCA-2013-4-1386 (Project 185/2014) and PN-II-PT-PCCA-2013-4-1407 (Project 190/2014) financed by Executive Agency for Higher

\*, Iulia Solomon2

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[3] Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: Incidence.

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Squamous Cell Carcinoma: Biomarkers and Potential Therapeutic Targets

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

, Mihaela Adriana Ilie<sup>1</sup>

,

149

Regarding the molecular aspects of cutaneous SCC, studies have shown not only the high levels of complement factor H and factor H-like protein 1 mRNA in comparison with normal skin, but also stronger expression in SCC than *in situ* carcinoma or actinic keratosis. In addition, it was demonstrated that knocking down CFH and FHL-1 lead to the inhibition of proliferation and migrations of SCC cells, suggesting their importance as progression markers and potential therapeutic targets in skin SCC.

An important aspect in risk evaluation for SCC is the integrity of immune systems. The high incidence of this malignancy in patients with compromised immune system was observed, pointing out the role of HLA system which varies between immunocompetent and immunosuppressed patients.

Other biomarkers involved in SCC development and progression are MMPs, serine peptidase and their inhibitors (Serpin-A1 being associated with tumorigenic change of keratinocytes and tumor progression). The metastatic prediction is attributed to EGFR and nuclear active IκB kinase (IKK) expression, thus a promising cSCC therapy is represented by EGFR inhibitors.

Oral squamous cell carcinoma is associated with EGFR that not only activates the proteintyrosine kinase system involved in cell multiplication and differentiation, but also plays an important role in OSCC resilience to radiotherapy. Others biomarkers associated with OSCC are p53/p63 and Bcl-2. Tumor invasion is correlated with both matrix degradation enzymes and cell adhesion proteins.

Genital squamous cell carcinoma is linked with p16 (in less aggressive form of vulvar SCC), p53 (weaker prognosis), cofilin-1, galectin-7 and weel. HPV infection plays an important role in SCC induction and evolution through the deactivation of tumor suppression genes by E6 and E7. Increased Hsp70 is also increased in this type of cancer.

Overall, skin cell carcinoma is one of the most frequent malignancy worldwide that even if it is easily treated and the cure rate is high, there are cases when metastasize can occur. An accurate clinical exam correlated with histological, immunohistochemical and proteomic investigation can establish the biomarkers involved in the development and evolution of this malignancy and reveal the appropriate treatment strategy for each patient.

Due to the fact that SCC is associated with frequent recurrence and sometimes metastasis, it is necessary to realize the study of biological transformation that occurs in these types of cancers. The discovery of various biomarkers can outline the occurrence, evolution and the prognosis of this keratinocyte-derived tumor.

It is important to focus on the analysis of normal, inflammatory and malignant keratinocyte proteome in order to determine novel biomarkers that are associated with the development and progression of SCC and therefore can be used in the early detection, risk assessment, tumor monitoring and also discovery of new therapies for these patients.
