Squamous Cell Carcinoma Formation Research Articles

Updating the biologically based dose-response model for the nasal carcinogenicity of inhaled formaldehyde in the F344 rat.

Chronic inhalation of formaldehyde by F344 rats causes nasal squamous cell carcinoma (SCC). This outcome is well-characterized: including dose-response and time course data for SCC, mechanistic endpoints, and nasal dosimetry. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) used these resources to develop a biologically based dose-response (BBDR) model for SCC in F344 rats. This model, scaled up to humans, has informed dose-response conclusions reached by several international regulatory agencies. However, USEPA concluded that uncertainties precluded its use for cancer risk assessment. Here, we describe an updated BBDR model that addresses uncertainties through refined dosimetry modeling, revised analysis of labeling index data, and an extended dataset where both inhaled (exogenous) and endogenous formaldehyde (exogF, endoF) form DNA adducts. Further, since Conolly et al. (ibid) was published, it has become clear that, when controls from all F344 inhalation bioassays are considered, accounting for over 4000 rats, at most one nasal SCC occurred. This low spontaneous incidence constrains possible contribution of endoF to the formation of nasal SCC via DNA reactivity. Further, since both exogF and endoF form DNA adducts, this constraint also applies to exogF. The revised BBDR model therefore drives SCC formation through the cytotoxicity of high concentration exogF. An option for direct mutagenicity associated with DNA adducts is retained to allow estimation of an upper bound on adduct mutagenicity consistent with the lack of a spontaneous SCC incidence. These updates represent an iterative refinement of the 2003 model, incorporating new data and insights to reduce identified model uncertainties.

A TNFR1–UBCH10 axis drives lung squamous cell carcinoma dedifferentiation and metastasis through a cell-autonomous signaling loop

Tumor necrosis factor receptor 1 (TNFR1), encoded by TNFRSF1A, is a critical transducer of inflammatory pathways, but its physiological role in human cancer is not completely understood. Here, we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-dead Ikkα knock-in (KA/KA) mice. Knocking out Tnfrf1a in KA/KA mice blocked lung SCC formation. When injected via tail vein, KALLU+ lung SCC cells that highly expressed TNFR1/TNF, Sox2, c-Myc, Twist1, Bcl2, and UBCH10, generated dedifferentiated spindle cell carcinomas with epithelial–mesenchymal transition markers in mouse lungs. In contrast, KALLU+ cells with silenced TNFR1 and KALLU- cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10, an E2 ubiquitin-conjugating enzyme with targets including Twist1, c-Myc, and Sox2, which enhanced SCC cell dedifferentiation. Furthermore, Tg-K5.TNFR1;KA/KA mice, which expressed transgenic TNFR1 in keratin 5-positve epithelial cells, developed more poorly differentiated and metastatic lung SCCs than those found in KA/KA mice. These findings demonstrate that an overexpressed TNFR1–UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may contribute to the development of differentiation-related therapies for lung SCC.

Abstract 98: The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment

Abstract BRAF inhibitor (BRAFi) therapies are highly effective treatments for metastatic melanoma. However, BRAFi monotherapies are associated with a significant risk of squamous cell carcinoma (SCC) development in melanoma patients. Consequently, BRAF inhibition results in an unanticipated activation of the MAPK pathway in surrounding cells that harbour wildtype BRAF. Fortunately, a combination approach with both a BRAFi and the selective MAPK inhibitor (MEKi), trametinib, attenuates BRAFi-induced risk of SCCs. Despite the fact that this combination therapy is widely used in clinical practice, the mechanisms associated with SCC induction and why this effect is attenuated with a MEK inhibitor remain poorly understood. HORMAD1, a meiosis specific gene, has been shown to have an impact on genomic instability and proliferation in the development of SCCs. Moreover, recent work in our lab has demonstrated that the MAPK pathway regulates HORMAD1 expression in SCC cell lines. Therefore, we sought to investigate a potential role of HORMAD1 in the risk and development of SCCs as a mechanism of BRAFi that is attenuated with the co-administration of the MEKi, trametinib. Using the BRAFi, vemurafenib, we inhibited the kinase activity of activated BRAF (V600E) and the MEKi, trametinib to evaluate the expression of HORMAD1 in melanoma and normal keratinocyte cell lines. To determine the effects of these two inhibitors, a cell proliferation assay was conducted followed by the evaluation of various components of cell cycle regulation and genomic instability. We found that HORMAD1 protein expression levels increased following treatment with the BRAFi, vemurafenib, in the normal keratinocyte cell line, HaCaT, but not in the melanoma cell line, A375. In contrast, HORMAD1 expression decreased following treatment with the MEKi, trametinib in both HaCaT and A375. Cell proliferation assays depict a vulnerability to both vemurafenib and trametinib in both normal and melanoma cell lines, however, HaCaT cells appear to be more susceptible to increased levels of genomic instability following treatment with vemurafenib when compared to A375. Our results suggest that HORMAD1 likely plays a key role in the development of SCCs by increasing genomic instability and proliferation in normal keratinocytes following BRAFi monotreatment. The increased risk of SCC formation is attenuated by dampening HORMAD1 levels with the co-administration of the MEKi, trametinib. Citation Format: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov. The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 98.

Repeated exposure of the oral mucosa over 12\xa0months with cold plasma is not carcinogenic in mice

Peri-implantitis may result in the loss of dental implants. Cold atmospheric pressure plasma (CAP) was suggested to promote re-osseointegration, decrease antimicrobial burden, and support wound healing. However, the long-term risk assessment of CAP treatment in the oral cavity has not been addressed. Treatment with two different CAP devices was compared against UV radiation, carcinogen administration, and untreated conditions over 12 months. Histological analysis of 406 animals revealed that repeated CAP exposure did not foster non-invasive lesions or squamous cell carcinoma (SCCs). Carcinogen administration promoted non-invasive lesions and SCCs. Molecular analysis by a qPCR screening of 144 transcripts revealed distinct inflammatory profiles associated with each treatment regimen. Interestingly, CAP treatment of carcinogen-challenged mucosa did not promote but instead left unchanged or reduced the proportion of non-invasive lesions and SCC formation. In conclusion, repeated CAP exposure of murine oral mucosa was well tolerated, and carcinogenic effects did not occur, motivating CAP applications in patients for dental and implant treatments in the future.

286 HORMAD1 Contributes to the Development of Squamous Cell Carcinomas in Melanoma Patients

BRAF inhibitor (BRAFi) therapies are effective treatments for metastatic melanoma. However, BRAFi monotherapies are associated with a significant risk of squamous cell carcinoma (SCC) in melanoma patients. Consequently, BRAF inhibition results in an activation of the MAPK pathway in cells that harbour wildtype BRAF. Fortunately, a combination approach with both a BRAFi and the selective MAPK inhibitor (MEKi), trametinib, attenuates BRAFi-induced risk of SCCs. Despite the wide use of this therapy, the mechanisms associated with SCC induction remain poorly understood. HORMAD1, a meiosis gene, has been shown to have an impact on genomic instability and proliferation in the development of SCCs. Recent work has shown that HORMAD1 expression is regulated by the MAPK pathway in SCC cell lines. Therefore, we sought to investigate a potential role of HORMAD1 in the risk and development of SCCs that is attenuated with the administration of the MEKi, trametinib. We used BRAFi, vemurafenib and the MEKi, trametinib to evaluate the expression of HORMAD1 in melanoma and normal keratinocyte cell lines. To determine the effects of the two inhibitors, a cell proliferation assay was conducted followed by the evaluation of various components of cell cycle regulation and genomic instability. We found that HORMAD1 protein expression increased following treatment with vemurafenib in normal keratinocytes but not in a melanoma cells. In contrast, HORMAD1 expression decreased following treatment with trametinib in both HaCaT and A375. Cell proliferation assays depict a vulnerability to both vemurafenib and trametinib in both normal and melanoma cell lines, however, HaCaT cells appear to be more susceptible to increased levels of genomic instability following treatment with vemurafenib. Our results suggest that HORMAD1 likely plays a key role in the development of SCCs by increasing genomic instability and proliferation in normal keratinocytes following BRAFi monotreatment. The increased risk of SCC formation is attenuated by dampening HORMAD1 levels with the co-administration of the MEKi, trametinib.

Histopathological effect of pterostilbene as chemoprevention in N-nitroso-tri-chloroethylurea (NTCU)-induced lung squamous cell carcinoma (SCC) mouse model.

Lung cancer is the leading cause of cancer-related deaths, and squamous cell carcinoma (SCC) is one of the most common types of lung cancer. Chemoprevention of lung cancer has gained increasing popularity as an alternative to treatment in reducing the burden of lung cancer. Pterostilbene (PS) may be developed as a chemopreventive agent due to its pharmacological activities, such as anti-proliferative, anti-inflammatory and antioxidant properties. This study aimed to investigate the effect of PS on the development of lung SCC in the mouse model. A total of 24 seven-week-old female Balb/C mice were randomly categorised into four groups, including two control groups comprising the N-nitroso-trischloroethylurea (NTCU)-induced lung SCC and vehicle control (VC) groups and two treatment groups comprising the 10mg/kg PS (PS10) and 50mg/kg PS (PS50) groups. All lung organs were harvested at week 26 for histopathological analysis. All PS treatment groups showed chemopreventive activity by inhibiting the progression of lung SCC formation with PS10, resulting in mild hyperplasia, and PS50 was completely reversed in the normal bronchial epithelium layer compared with the VC group. PS treatment also reduced the expression of cytokeratin 5/6 in the bronchial epithelium layer. Both PS10 and PS50 significantly reduced the epithelium thickness compared to the NTCU group (p<0.05). PS is a potential chemopreventive agent against lung SCC growth by suppressing the progression of pre-malignant lesions and reducing the thickness of the bronchial epithelium. The underlying molecular mechanisms of PS in lung SCC should be further studied.

Abstract 6139: Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice

Abstract A historical over-reliance on male animals in research studies has clouded sex differences in pathologic diseases. This led to a mandate from the NIH requiring the use of both male and female animals in preclinical studies. Our study began with the aim to evaluate both sexes of KC mice (LSL-KrasG12D/+; Pdx1-Cre), a standard pre-clinical model for pancreatic ductal adenocarcinoma (PDAC). This was because previous characterization of this model to advanced age (9-12 months) only included males, and evaluating both sexes was an essential foundation for subsequent studies of PDAC progression. Twenty-eight KC mice have been evaluated, comprised of 15 males and 13 females. KC mice developed the expected pancreatic cancer pre-cursor lesions called PanINs (100% PanIN1, 7% PanIN 2 and 7% PanIN 3) and PDAC (14%) at an established time point (age 9 months). Surprisingly, female KC mice developed anal lesions, a finding that has not previously been described. Histopathologic analysis demonstrated anal squamous cell carcinoma (SCC), with all 13 KC females developing anal SCC compared to 0/15 in KC males and 0/83 control mice (Table 1). Genotyping for activated Kras mutation confirmed the presence of KrasG12D, indicating Pdx1 expression (Pdx1-Cre) in the anal tumor tissue. To understand the distinct sex differences and connection to sex-dependent steroids (estrogen and testosterone), female mice were ovariectomized (n = 5) and males castrated (n = 6). Remarkably, while 5/5 females developed anal SCC (i.e. unchanged phenotype), 6/6 males developed anal SCC, a stark contrast to the absence of tumor development in non-castrated KC males. This suggests a novel mechanism in which Kras driven anal SCC tumor development is suppressed through testosterone / dihydrotestosterone (DHT) exposure. Follow-up studies will focus on the mechanism by which testosterone or DHT suppresses Kras-driven anal SCC formation. These findings may ultimately have therapeutic implications for the subset of patients with Kras-mutant anal SCC. Table 1:Characterization and Incidence of Anal SCC TumorsGroupMouseAnal SCC IncidenceControlC57Bl6 Male (n=12)0/12 (0%)ControlC57Bl6 female (n=11)0/11 (0%)ControlKrasG12D/+ Female (n=9)0/9 (0%)ControlKrasG12D/+ Male (n=18)0/18 (0%)ControlPDX1-Cre male (n=10)0/10 (0%)ControlPDX1-Cre Female (n=23)0/23 (0%)KC MiceKC Male (n=15)0/15 (0%)KC MiceKC Female (n=13)13/13 (100%)Study KC MiceCastrated KC Male (n=6)6/6 (100%)Study KC MiceOvariectomized KC Female (n=5)5/5 (100%) Citation Format: Morgan Walcheck, Jessica Noel, Manabu Nukaya, Kristina Matkowskyj, Sean Ronnekleiv-Kelly. Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6139.

Dysregulated Tgfbr2/ERK-Smad4/SOX2 Signaling Promotes Lung Squamous Cell Carcinoma Formation.

Lung squamous cell carcinoma (SCC) is a common type of lung cancer. There is limited information on the genes and pathways that initiate lung SCC. Here, we report that loss of TGFβ type II receptor (Tgfbr2), frequently deleted in human lung cancer, led to predominant lung SCC development in KrasG12D mice with a short latency, high penetrance, and extensive metastases. Tgfbr2-loss-driven lung SCCs resembled the salient features of human lung SCC, including histopathology, inflammatory microenvironment, and biomarker expression. Surprisingly, loss of Smad4, a key mediator of Tgfbr2, failed to drive lung SCC; instead, low levels of phosphorylated ERK1/2, a Smad-independent downstream effector of Tgfbr2, were tightly associated with lung SCC in both mouse and human. Mechanistically, inhibition of phosphorylated ERK1/2 significantly upregulated the expression of SOX2, an oncogenic driver of lung SCC, and cooperated with SMAD4 repression to elevate SOX2. Inhibition of ERK1/2 in Smad4fl/fl ;KrasG12D mice led to extensive lung SCC formation that resembled the SCC phenotype of Tgfbr2-deficient mice. Overall, we reveal a key role of ERK1/2 in suppressing SCC formation and demonstrate that dysregulated Tgfbr2/ERK-Smad4/SOX2 signaling drives lung SCC formation. We also present a mouse model of metastatic lung SCC that may be valuable for screening therapeutic targets. SIGNIFICANCE: This study sheds new light on the mechanisms underlying lung SCC formation driven by mutated Kras.

Innumerable squamous cell carcinomas in a Vietnam War veteran exposed to chemical defoliants

Objective. We present a successful multidisciplinary treatment approach used for a patient with rapidly developing, high-volume, and high-risk squamous cell carcinomas (SCCs), addressing short-term treatment, long-term maintenance, and appropriate preventative strategies in a difficult patient population. Case report. An immunocompetent, 84-year-old, Caucasian man with at least 30 SCCs of the scalp, head, neck, and upper extremities, including a 4-cm SCC on the vertex of the scalp infiltrating to the periosteum, presented to a cutaneous oncology clinic. Initial physical examination revealed nearly confluent, erythematous, hyperkeratotic, crusted papules and plaques on the head, neck, back, arms, and dorsal hands, all of which were clinically obvious SCC. Nonlesional skin displayed widespread epidermal dysplasia. The patient was seen by the clinic's medical oncology and dermatology teams in coordinated dual visits. The invasive scalp lesion was treated by Mohs surgery and radiation, and the large SCC and field cancerization were successfully treated with a combination of topical and intralesional 5-fluorouracil with pulsed oral capecitabine, which resulted in a significant reduction in SCC disease burden. Conclusion. Management of patients with overwhelming numbers of SCCs is extremely challenging. Combination topical and/or intralesional 5-fluorouracil and oral capecitabine may be considered as part of the management approach when mechanical destruction and surgery alone are not feasible. Multidisciplinary care coordinated between the surgeon, dermatologic oncologist, medical oncologist, and radiation oncologist is essential for providing comprehensive treatment and deploying preventative strategies in this population at high risk for metastatic SCC formation.

MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB-E2F1/cyclin A2 axis.

Patients with cervical cancer have abnormal cell proliferation and invasion after many years of latency. However, the precise mechanisms remain unclear. Mitogen- and stress-activated kinase 2 (MSK2) is a serine/threonine kinase which displays a phenotype that promotes tumor growth and metastasis in many different types of tumors. The aim of the present study was to determine the effects of MSK2 on the proliferation of cervical cancer cells and elucidate the signaling pathways through which MSK2 exerts its effects in the pathogenesis of squamous cell carcinoma (SCC). Our results confirmed that MSK2 expression was significantly upregulated in cervical cancer cells both in vivo and in vitro. We further found that the expression patterns of paired-box gene 8 (PAX8) and MSK2 were positively correlated in cervical cancer specimens. Moreover, MSK2 knockdown inhibited the phosphorylation of PAX8 and retinoblastoma protein (RB), and suppressed the sequential expressions of cell proliferation factors E2F1 and cyclin A2, resulting in the inhibition of SCC cell proliferation and tumor formation. Thus, this study demonstrates that MSK2 has oncogenic effects in the formation and development of SCC via the PAX8/RB-E2F1/cyclin A2 axis.

De Novo PITX1 Expression Controls Bi-Stable Transcriptional Circuits to Govern Self-Renewal and Differentiation in Squamous Cell Carcinoma.

Basal tumor propagating cells (TPCs) control squamous cell carcinoma (SCC) growth by self-renewing and differentiating into supra-basal SCC cells, which lack proliferative potential. While transcription factors such as SOX2 and KLF4 can drive these behaviors, their molecular roles and regulatory interactions with each other have remained elusive. Here, we show that PITX1 is specifically expressed in TPCs, where it co-localizes with SOX2 and TRP63 and determines cell fate in mouse and human SCC. Combining genetargeting with chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptomic analysesreveals that PITX1 cooperates with SOX2 and TRP63 to sustain an SCC-specific transcriptional feed-forward circuit that maintains TPC-renewal, while inhibiting KLF4 expression and preventing KLF4-dependent differentiation. Conversely, KLF4 represses PITX1, SOX2, and TRP63 expression toprevent TPC expansion. This bi-stable, multi-inputnetwork reveals a molecular framework that explains self-renewal, aberrant differentiation, and SCCgrowth in mice and humans, providing clues for developing differentiation-inducing therapeutic strategies.

Pten loss in Lgr5+ hair follicle stem cells promotes SCC development

Accumulating data support that tissue stem cells give rise to cancer cells. Hair follicle stem cells (HFSCs) undergo cyclic quiescence and activation and may sever as the origin of cutaneous squamous cell carcinoma (SCC). Pten is a tumor suppressor gene that is frequently mutated in hereditary cancer syndromes such as Cowden disease, which is featured with papillomatosis in cutaneous tissues and hyperkeratosis in the acral region of the skin. Additionally, mice with keratinocyte-specific Pten deficiency (k5-Pten-/- mice) show epidermal hyperplasia and spontaneous tumor formation. However, the impact of Pten mutation in HFSCs, such as in Lgr5+ HFSCs, on SCC formation is unclear.Methods: We established experiments with wildtype and Lgr5-CreER; Ptenflox/flox mice, and used DMBA/TPA two-stage skin carcinogenesis model to explore the effect of Pten loss in Lgr5+ HFSCs of 3 weeks old mice in skin carcinogenesis. In vitro experiments (cell culture and protein expression analysis) are employed to investigate molecular mechanisms involved.Results: Pten loss in Lgr5+ HFSCs promoted SCC formation, which was attenuated in TNF-/- mice. Notably, β-catenin loss in Lgr5+ HFSCs decreased the formation of SCC. In addition, Pten loss in cultured epidermal stem cells upregulated the levels of both phospho-Akt and β-catenin.Conclusion: Pten loss in Lgr5+ cells induced Akt/β-catenin signaling, and SCCs can subsequently be raised as progeny from these primed Lgr5+ stem cells.

YAP drives cutaneous squamous cell carcinoma formation and progression.

Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.

Deciphering the cells of origin of squamous cell carcinomas.

Squamous cell carcinomas (SCCs) are among the most prevalent human cancers. SCC comprises a wide range of tumours originated from diverse anatomical locations that share common genetic mutations and expression of squamous differentiation markers. SCCs arise from squamous and non-squamous epithelial tissues. Here, we discuss the different studies in which the cell of origin of SCCs has been uncovered by expressing oncogenes and/or deleting tumour suppressor genes in the different cell lineages that compose these epithelia. We present evidence showing that the squamous differentiation phenotype of the tumour depends on the type of mutated oncogene and the cell of origin, which dictate the competence of the cells to initiate SCC formation, as well as on the aggressiveness and invasive properties of these tumours.

Skin Stem Cells in Silence, Action, and Cancer.

In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoveries equally deserving of this award.

Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis

Human lung squamous cell carcinoma (SCC) is highly associated with increased pulmonary macrophage infiltration. Previously, we showed that marked pulmonary infiltrating macrophages were required for spontaneous lung SCC development in a mouse model (L-IkkαKA/KA, KA/KA) that resembles human lung SCC. Interestingly the lung SCC-associated macrophages specifically express elevated inducible nitric oxide synthase (NOS2). However, the role of macrophage NOS2 in lung carcinogenesis has not been explored. Here, we show that NOS2 ablation inhibits macrophage infiltration, fibrosis, and SCC development in the lungs of KA/KA mice. Macrophage NOS2 was found to circulate inflammation and enhance macrophage migration and survival. NOS2 promotes foamy macrophage formation characterized with impaired lipid metabolism. NOS2 null bone marrow transplantation reduces foamy macrophage numbers and carcinogenesis in KA/KA chimaeras. This finding sheds light on a new mechanism by which macrophage NOS2 increases pulmonary inflammatory responses and macrophage survival and impairs macrophage lipid metabolism, thereby promoting lung SCC formation.

Deciphering the cells of origin of squamous cell carcinomas

Squamous cell carcinomas (SCCs) are among the most prevalent human cancers. SCC comprises a wide range of tumours originated from diverse anatomical locations that share common genetic mutations and expression of squamous differentiation markers. SCCs arise from squamous and non-squamous epithelial tissues. Here, we discuss the different studies in which the cell of origin of SCCs has been uncovered by expressing oncogenes and/or deleting tumour suppressor genes in the different cell lineages that compose these epithelia. We present evidence showing that the squamous differentiation phenotype of the tumour depends on the type of mutated oncogene and the cell of origin, which dictate the competence of the cells to initiate SCC formation, as well as on the aggressiveness and invasive properties of these tumours.

PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis.

Squamous cell carcinoma (SCC) of the skin is a keratinocyte malignancy characterized by tumors presenting on sun-exposed areas with surgery being the mainstay treatment. Despite advances in targeted therapy in other skin cancers, such as basal cell carcinoma and melanoma, there have been no such advances in the treatment of SCC. This is partly due to an incomplete knowledge of the pathogenesis of SCC. We have recently identified a protein kinase C-associated kinase (PKK) as a potential tumor suppressor in SCC. We now describe a novel conditional PKK knockout mouse model, which demonstrates that PKK deficiency promotes SCC formation during chemically induced tumorigenesis. Our results further support that PKK functions as a tumor suppressor in skin keratinocytes and is important in the pathogenesis of SCC of the skin. We further define the interactions of keratinocyte PKK with TP63 and NF-κB signaling, highlighting the importance of this protein as a tumor suppressor in SCC development.

Molecular effects of hesperetin, a citrus flavanone on7,12-dimethylbenz(a)anthracene induced buccal pouch squamous cell carcinoma in golden Syrian hamsters

In recent years, researchers have been focused on citrus flavanone, a naturally occurring bioactive substance of hesperetin. To investigate the molecular mechanism based chemopreventive efficacy of hesperetin on 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch (HBP) squamous cell carcinoma (SCC). The oral tumour was provoked by painted with 0.5% DMBA on left buccal pouch thrice a week for 10 consecutive weeks developed well-differentiated SCC and tumour formation was 100% in DMBA alone. We evaluated the chemopreventive potential of hesperetin by assessing the lipid peroxidation (LPO) by-products, status of enzymatic, non-enzymatic antioxidants, detoxifying agents etc. Moreover, modulating expression of apoptotic and cell proliferation markers were observed in HBP SCC experimental hamsters. Oral administration of hesperetin (20 mg/kg b.w.) to DMBA painted hamsters significantly reversed the stages of oral SCC. Our findings indicate that hesperetin possesses a chemopreventive effect in DMBA-induced oral SCC by exerting anti-carcinogenic property.

P63 in Squamous Cell Carcinoma of the Skin: More Than a Stem Cell/Progenitor Marker

The p63 gene is often overexpressed in squamous cell carcinomas; however, how its overexpression contributes to tumor formation and expansion is still incompletely understood. Devos etal. report the development of a versatile mouse model demonstrating that p63 facilitates squamous cell carcinoma formation in skin and providing an excellent tool to dissect the relevance of its downstream signaling pathways in tumorigenesis.