**8. Biomarkers of oral SCC**

[87, 88]. In immunosuppressed HPV-infected patients, it was reported a notable HLA I—SCC connection, probably due to the fact that HLA I processes and presents intracellular peptide antigens, including viral proteins, and thus HPV could be a co-factor of tumorigenesis [87].

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

Alterations in the composition of basement membrane and dermal extracellular matrix of premalignant lesions are early events in cSCC progression. An influx of inflammatory cells promotes the secretion of proteases, which in turn regulates the availability of growth factors, cytokines, and chemokines and thus influences the growth and invasion of cSCC. Later, the number of inflammatory cells increases with cSCC progression, and the expression of complement factors and inhibitors by tumor cells is induced (CFI, CFH, FHL-1) [89]. A fine interplay between matrix metalloproteinases (MMPs) and their inhibitors could settle the scene for discovering new targets and prognostic or monitoring predictors of the disease. As in cutaneous melanoma, where the role played by MMPs in the phenomenon of regression is an actual approach [90], in SCC, the cellular enzymatic portfolio is a good pool for emerging novel targets coupled to novel biomarkers. For instance, upregulation of MMP-7 expression has also been registered in cSCC, especially in the tumor invasive edge, and moreover activates heparin-binding epidermal growth factor-like growth factor (HB-EGF) promoting cellular proliferation [91] and thus suggesting a future therapeutic effect of HB-EGF antagonists

Serine peptidase and their inhibitors (Serpins) are also considered useful for biomarker monitoringing of cSCC progression. Studies performed on serpin family gene expression levels in cSCC cell lines versus normal keratinocytes demonstrate a significantly raised Serpin-A1 expression correlated with the tumorigenic change of keratinocytes [92]. *In vivo* studies correlate Serpin-A1 expression with tumor progression in SCC tumor cells. By using a chemically induced skin carcinogenesis mouse model, as a valuable tool in completing cancer progression profile [23] it was checked the correlation of Serpin-A1 expression with progression of mouse skin SCC [92], suggesting that Serpin-A1 may serve as an useful biomarker for monitoring cSCC progression. Maspin is another member of serpin family—an inhibitor of mammary serine protease—reported as a tumor suppressor in various cancers. Real-time PCR and Western blotting analysis found that Maspin was downregulated in the cSCC tissues compared with the nearby normal tissues. Studies performed on A431 cell line revealed that overexpression of Maspin inhibits growth, cellular proliferation and enhances A431 cells apoptosis by increasing PARP and Bax expression, while decreasing Bcl-2 expression. Therefore, Maspin

analysis may provide new insights in the diagnosis and therapy of cSCC [93].

New potential classes of agents for cSCC are also directed to counteract the metastatic feature of this tumor which represents a difficult challenge, knowing that metastatic cSCC has a mortality rate of over 70%. As a comprehensive chemotherapeutic approach in the metastatic form is still lacking, new molecular insights are to be done. Recently, expression of EGFR and nuclear active IκB kinase (IKK) was proved to have a role in metastatic prediction. Thus, a newer and more promising class of agents for metastatic cSCC therapy is represented by EGFR inhibitors. Other advances in finding novel treatments for metastatic cSCC are related to p53 studies, epigenetic approaches such as hypermethylation of specific genes, chromatin remodeling, and the RAS/RTK/PI3K pathway [94]. Molecules with well-established roles in

in advanced cSCC [12].

Despite recent advances in diagnosis and therapy, OSCC is still one of the most difficult malignancies to handle due to its great invasive potential both locally and at lymphatic level (in the cervical lymph nodes) [98]. Its occurrence varies across the world as it is closely linked to diet and lifestyle choices (alcohol and cigarettes). OSCC occurs as a result of squamous cells genetic mutations, the new cells developing multiplicative and invasive characteristics [99]. Its genetic heterogeneity can be later highlighted by the fact that many tumors, at a similar stage and location, present significant clinical differences and they can react very differently to treatment. Although the therapeutic strategies are in a permanent development, the survival rate of OSCC patients remains low. It has also been found that predicting treatment outcome using conventional clinical and histopathological parameters carry a low success rate.

It is clear that histopathology remains to this day the benchmark decision-making process as far as diagnosis and treatment are concerned. However, recent molecular studies have made significant progress in understanding and identification of those biomarkers best placed to predict OSCC aggression. Attempts have been made to refine histopathological analysis with immunohistochemistry; this detects gene composition at protein level and brings forward several prognostic tumor biomarkers associated with OSCC's clinical outcome. As such, tumor suppressor genes, oncogenes, angiogenic markers, cell adhesion molecules and cell proliferation markers have been discovered to be potential tools that could help to predict the outcome of OSCC patients [99]. Therapeutic management through molecular inhibition directed at those biomarkers associated with radiotherapy and/or adjuvant chemotherapy are promising treatments for OSCC patients.

EGFR is a transmembrane cell-surface receptor that binds to ligands such as EGF and TGF-α and is one of the most studied OSCC biomarkers. It triggers the activation of the protein-tyrosine kinase system, which acts as a regulator of the signaling process linked to cell multiplication and differentiation [100]. It plays a significant role in OSCC's resilience to radiotherapy.

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 significance to OSCC.

that lymphatic invasion and poor tumor differentiation correlate with downregulation of galactin-7 and wee1 [120, 121]. A very important role is played by cofilin which has major implications in carcinogenesis and vulvar SCC invasion [122]. This has turned it into a therapeutic option as it significantly reduces tumor progression. Also, other reports worthy to be considered indicate that downregulation of galectin-7 and high wee1 expressions have been

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Regarding treatment options, surgical resection is associated with a high mortality rate; therefore, attempts are being made to avoid and replace it with radiotherapy associated with chemotherapy [123, 124]. Due to limited options available, there is a real need for new targeted

SCC with penile localization (PSCC) has a relatively low incidence and is associated with poor hygiene, lack of circumcision, HPV infection, and tobacco use [122, 125–127]. Much the same as vulvar SCC, HPV infections play an important role. Starting with the HPV DNA incorporation step into the human genome, E6 and E7 genes deactivate tumor-suppressing genes. Due to the low occurrence rate of PSCC, there are not many studies looking at this type of cancer. These studies have found an increased concentration of Hsp70 [128]. Although not specific to PSCC and present in other types of cancer such as breast, colon, liver, and prostate cancer [129], it is believed to play a protective role for the tumor cells and is thus involved in carcinogenesis. A study looking at families of plaque molecules involved in the binding of filaments, desmosomes, and hemidesmosomes [130] has linked poor expression of plectin (a cytolinker of this family) with rapid cancer progression [131]. Since the diagnosis of inguinal metastases is currently the most important prognostic factor, the discovery of other biomarkers involved

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

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

correlated with an increased metastasis risk [120, 121].

therapies being developed grounded on specific biomarkers.

in a possible therapeutic management is imperative [128].

are also interfering in the keratinocyte differentiation and proliferation.

**10. Conclusions**

with significant cell differentiation.

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 OSCC patients [102–104].

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 vasculature [108, 109].

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