Majority Of Basal Cell Carcinomas Research Articles

COL10A1 expression distinguishes a subset of cancer-associated fibroblasts present in the stroma of high-risk basal cell carcinoma.

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer and the most common malignancy in humans. Different morphological subtypes of BCC are associated with low- or high-risk of recurrence and aggressiveness, but the underlying biology of how the individual subtypes arise remains largely unknown. Because the majority of BCCs appear to arise from mutations in the same pathway, we hypothesized that BCC development, growth and invasive potential is also influenced by the tumor microenvironment and in particular by cancer-associated fibroblasts (CAFs) and their secreted factors. We aimed to characterize the stroma of the different BCC subtypes with a focus on CAF populations. To investigate the stromal features of the different BCC subtypes, we applied laser-capture microdissection (LCM) followed by RNA sequencing. A cohort of 15 BCC samples from 5 different "pure" subtypes (superficial, nodular, micronodular, sclerosing and basosquamous; n=3 each) were selected and included in the analysis. Healthy skin was used as a control (n=6). We confirmed the results by immunohistochemistry. We validated our findings in two independent, public single-cell RNA sequencing (scRNAseq) datasets and by RNAscope. The stroma of the different BCC subtypes have distinct gene expression signatures. Nodular and micronodular seem to have the most similar signatures, while superficial and sclerosing the most different. By comparing low- and high-risk BCC subtypes, we observed that Collagen 10A1 (COL10A1) is overexpressed in the stroma of sclerosing/infiltrative and basosquamous but not micronodular high-risk subtypes. Those findings were confirmed by immunohistochemistry in a cohort of 89 different BCC and 13 healthy skin samples. Moreover, scRNAseq analysis of BCCs of two independent datasets showed that the COL10A1-expressing population of cells is associated with the stroma adjacent to invasive BCC and shows extracellular matrix remodeling features. We identified COL10A1 as a marker of high-risk BCC, in particular of the sclerosing/infiltrative and basosquamous subtypes. We demonstrated at the single cell level that COL10A1 is expressed by a specific CAF population associated with the stroma of invasive BCC. This opens up new tailored treatment options as well as a new prognostic biomarker for BCC progression.

Basal cell carcinoma in a non-sun exposed site: A rare case report

Basal cell carcinoma (BCC) is the most common cutaneous malignancy and accounts for approximately 80% of all non-melanoma skin cancers. BCCs develop characteristically on sun-exposed areas, with around 85% of reported cases developing over the head or neck. This carcinoma can arise, in non-sun-exposed areas also, such as the axilla, nipple, and the genital and perianal areas. In India and in black population, basal cell carcinoma is a rare form of cutaneous malignancy. The majority of BCC are treated surgically, with peripheral margins of 2 to 5 mm for low-risk tumours and 5 to 15 mm for high-risk lesions.

Indolactam Dipeptides as Nanomolar Gli Inhibitors.

The Gli transcription factors within the Hedgehog (Hh) signaling pathway play essential roles in human development. However, the reactivation of Gli proteins in adult tissue is tumorigenic and drives the progression of several cancers, including the majority of basal cell carcinomas. Here we describe a novel set of indolactam dipeptides that target protein kinase C (PKC), exploiting the unique capacity of PKC isozymes to act as regulators of Gli. We devised an efficient synthetic route for the indolactam-based natural product (-)-pendolmycin and a series of analogues, and we evaluated these analogues in mechanistically distinct Gli reporter assays. The lead compound from these studies, N-hexylindolactam V, exhibits superior Gli suppression relative to clinical inhibitors and blocks the growth of Gli-dependent basal cell carcinoma cells. More broadly, our structure-activity studies provide inroads for the development of novel Gli antagonists and new avenues for combating Gli-driven cancers.

Reflectance Confocal Microscopy Identification of Subclinical Basal Cell Carcinoma after Vismodegib Treatment: Report of a Case.

Although surgery represents the treatment of choice for the majority of basal cell carcinomas, different therapies are required to treat the advanced ones. Vismodegib and sonidegib are the two oral Smoothened (Smo) inhibitors approved for the treatment of advanced basal cell carcinoma. Clinical detection of subclinical basal cell carcinoma during and after vismodegib treatment could be difficult, requiring the use of dermoscopy and reflectance confocal microscopy as noninvasive diagnostic methods. We report the case of a 62-year-old woman with a locally advanced basal cell carcinoma successfully treated with vismodegib in which dermoscopy and reflectance confocal microscopy showed their superiority in detecting subclinical recurrent basal cell carcinoma developed on scar tissue after complete regression of the tumor.

Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened.

The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell specification, cell–cell interaction and tissue patterning during embryonic development. Canonical activation of HH-GLI signaling occurs through binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which derepresses the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO). Thus, active SMO initiates a complex intracellular cascade that leads to the activation of the three GLI transcription factors, the final effectors of the HH-GLI pathway. Aberrant activation of this signaling has been implicated in a wide variety of tumors, such as those of the brain, skin, breast, gastrointestinal, lung, pancreas, prostate and ovary. In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma. Besides the classical canonical ligand-PTCH1-SMO route, mounting evidence points toward additional, non-canonical ways of GLI activation in cancer. By non-canonical we refer to all those mechanisms of activation of the GLI transcription factors occurring independently of SMO. Often, in a given cancer type canonical and non-canonical activation of HH-GLI signaling co-exist, and in some cancer types, more than one mechanism of non-canonical activation may occur. Tumors harboring non-canonical HH-GLI signaling are less sensitive to SMO inhibition, posing a threat for therapeutic efficacy of these antagonists. Here we will review the most recent findings on the involvement of alternative signaling pathways in inducing GLI activity in cancer and stem cells. We will also discuss the rationale of targeting these oncogenic pathways in combination with HH-GLI inhibitors as a promising anti-cancer therapies.

A synthetic combinatorial approach to disabling deviant Hedgehog signaling

Mutations in components of the Hedgehog (HH) signal transduction pathway are found in the majority of basal cell carcinoma (BCC) and medulloblastoma incidents. Cancerous cells with intrinsic or acquired resistance to antagonists targeting the seven transmembrane effector Smoothened (SMO) frequently invoke alternative mechanisms for maintaining deviant activity of the GLI DNA binding proteins. Here we introduce a chemical agent that simultaneously achieves inhibition of SMO and GLI activity by direct targeting of the SMO heptahelical domain and the GLI-modifying enzymes belonging to the histone deacetylase (HDAC) family. We demonstrate a small molecule SMO-HDAC antagonist (IHR-SAHA) retains inhibitory activity for GLI transcription induced by SMO-dependent and -independent mechanisms frequently associated with cancer biogenesis. Synthetic combinatorial therapeutic agents such as IHR-SAHA that a priori disable cancer drivers and anticipated mechanisms of drug resistance could extend the duration of disease remission, and provide an alternative clinical development path for realizing combinatorial therapy modalities.

Guidelines of care for the management of basal cell carcinoma

Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.

Small Molecule Inhibitors of the Hedgehog Pathway in the Treatment of Basal Cell Carcinoma of the Skin.

Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials.

Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical usefulness.

Treatment of locally advanced basal cell carcinomas (laBCCs) with large, aggressive, destructive, and disfiguring tumors, or metastatic disease is challenging. Dysregulation of the Hedgehog (Hh) signaling pathway has been identified in the vast majority of basal cell carcinomas (BCCs). There are two United States Food and Drug Administration (US FDA)-approved Hh pathway inhibitors (HPIs) that exhibit antitumor activity in advanced BCC with an acceptable safety profile. Common adverse effects include muscle spasms, dysgeusia, alopecia, fatigue, nausea and weight loss.

Recurrence rates of periocular basal cell carcinoma following Mohs micrographic surgery: a retrospective study.

The incidence of basal cell carcinoma (BCC) has increased during the previous decade. Mohs micrographic surgery (MMS) is the gold standard technique for BCCs. The aim of this study was to investigate the recurrence rate of periocular BCCs following MMS in a regional Mohs treatment facility in the United Kingdom. The study comprised a retrospective case note review of 480 patients who underwent MMS from 2001 to 2006 for periocular BCC. Patients were identified via hospital coding databases. Medical records were reviewed, and the parameters collected include age, gender, previous BCCs and treatment modality, postoperative complications and subsequent management, site, size of lesion, histological subtype, and recurrence following MMS. Three hundred and ninety of the 480 patients identified were included. The remaining patients had died before the 5-year analysis (65), were lost to follow-up (20), or were identified as having Gorlin's syndrome (5). The majority of BCCs were 6-10 mm (42%) and nodular (45%). Six recurrences were identified (1.5%), including one (0.3%) primary BCC and five (6.5%) recurrent BCCs at the time of the MMS. The mean follow-up was 30 months (range 1-120 months). For BCC in the periocular region, MMS should be the treatment of choice for both primary and recurrent periocular BCCs. The increased recurrence rate, demonstrated by recurrent BCCs, highlights the need for a comprehensive follow-up.

Hedgehog Pathway Inhibition

The hedgehog (Hh) signaling pathway is aberrantly activated in a majority of basal cell carcinomas (BCC). Vismodegib and sonidegib are targeted inhibitors of Smoothened (SMO). Both drugs are approved for use in locally advanced BCC (laBCC), with vismodegib also approved for metastatic BCC (mBCC).

Discovery and Exploitation of Novel Targets by Approved Drugs

Discovery and Exploitation of Novel Targets by Approved Drugs

Appearance of cutaneous malignancies of the head and neck

The spectrum of cutaneous malignancies of the head and neck ranges from tumors that are fairly well behaved, such as the majority of basal cell carcinomas, to very aggressive cancers with a high metastatic rate, such as Merkel cell carcinoma. Most forms of cutaneous malignancy have characteristic clinical presentations, which assist in their clinical diagnosis. The goal of this article is to review the appearances and clinical presentations of common nonmelanoma skin cancers (basal and squamous cell carcinomas), uncommon nonmelanoma skin cancers (Merkel cell carcinoma and dermatofibrosarcoma protuberans), and the various subtypes of cutaneous melanoma.

Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through β-catenin signaling

Sonic hedgehog (Shh) signaling plays an important role in many human cancers and cancer stem cells. Here we investigate the activity and functional role of Shh signaling in chronic myeloid leukemia (CML) and leukemia progenitor cells. Differential activation of Shh signaling was found in about 50% CML chronic phase samples, about 70% of CML accelerated phase samples, and >80% CML blast crisis phase samples. Deregulated activation of Shh signaling was observed in CD34(+) and c-kit(+) leukemia progenitor cells. Stimulation of Shh signaling with exogenous Shh peptide induced expansion of CD34(+) and c-kit(+) progenitor cells (p < 0.05), inversely, blocking the pathway with signal inhibitor induced cell apoptosis (p < 0.05). Low level of Shh protein was observed in CML bone marrow stromal cells, and CD34(+) progenitor cells are less sensitive to exogenous Shh peptide and more sensitive to cyclopamine than CD34(-) cells (p < 0.05), implying cell-autonomous activation of Shh signaling play a predominant role in progenitor cells. Coactivation of Shh and β-catenin signaling was found in CD34(+) and c-kit(+) progenitor cells. Administration of Shh-neutralizing antibody or Wnt3a-neutralizing antibody in c-kit(+) progenitor cells induced cell apoptosis; however, Wnt3a peptide could salvage cell apoptosis, while Shh peptide failed to revert anti-Wnt3a-induced cell apoptosis. C-MYC, GLI1, BCL-2, and P21 were also found to be downstream targets of Shh signaling, mediating apoptosis or G(2)/M cell cycle arrest of progenitor cells. Our results demonstrate that autoactivated Shh signaling provides survival and proliferative cues in CML progenitor cells through downstream β-catenin signaling, suggesting a novel therapeutic approach in CML.

Basal cell carcinoma of the vulva: A case report

Basal cell carcinoma (BCC) is the most common human malignant neoplasm, accounting for 75% of all non-melanoma skin cancer. The incidence of BCC is strongly correlated with sun exposure as well as older age. Therefore, the vast majority of BCCs is observed in elderly patients on the sun-exposed skin of the head and neck with a frequency of more than 80%. BCC is very rare on sun-protected skin such as the per ianal and genital regions and other etiologic factors must be considered in these cases. Although the pathogenesis of vulvar BCC is unclear, early diagnosis is very important. Because BCC in these areas sometimes seems innocuous, it is recommended that a biopsy of all suspect lesions be perf ormed. We report a woman with BCC of the vulva treated with wide local resection and reviews the literatures on this subject.

Relationship between expression and methylation status of p16INK4a and the proliferative activity of different areas’ tumour cells in human colorectal cancer

The p16(INK4a) gene is a cell cycle inhibitor and a major tumour suppressor protein, but the regulation and effects on tumour cells' invasion process of p16(INK4a) is poorly known. A role for p16(INK4a) in basal cell carcinoma is suggested by the observation that p16(INK4a) was upregulated at the invasive front of the majority of basal cell carcinomas with infiltrative growth patterns, accompanied by cessation of proliferation. In this paper, we explore whether there is a difference of tumour cells' proliferative activity between the centre and the invasion front tissues of human colorectal cancer and its relationship with the expression and methylation status of p16(INK4a) gene. We obtained the centre and the invasion front tissues of colorectal cancer respectively by the technology of laser mircodissection. The expressions of the proliferating cell nuclear antigen ki67 and p16(INK4a) were assessed by immunohistochemistry, methylation-specific polymerase chain reaction (MS-PCR) and reverse-transcription polymerase chain reaction (RT-PCR) in the different areas. There was a significant difference in the expressions of ki67 between the centre and the invasion front tissues (p < 0.05). The difference did not correlate with age, sex, Dukes stage but did correlate with expression of p16(INK4a) gene (chi(2) = 25.37, p < 0.01). Furthermore, hypermethylation of the promoter was the major mechanism of inactivation of p16(INK4a) in the centre areas. Demethylation of the p16(INK4a) promoter, the elevated expression of p16(INK4a) protein and mRNA level was proved in the invasion front. Our finding suggested that enhanced invasion in tumours was accompanied by ceased proliferation in the invasion fronts of human colorectal cancer. This interesting phenomenon may be due to not only the microenvironment, but also the molecular changes such as p16(INK4a) status.

Basalzellkarzinom

Basal cell carcinoma is the most common human cancer. Its incidence is steadily increasing. The development of basal cell carcinoma is linked to genetic factors, including the individual skin phototype, as well as the cumulative exposure to UVB. The vast majority of basal cell carcinomas are sporadic tumors, while familial cases associated with certain hereditary syndromes are less common. At the molecular level, basal cell carcinomas are characterized by aberrant activation of sonic hedgehog signaling, usually due to mutations either in the ptch or smoh genes. In addition, about half of the cases carry mutations in the tp53 tumor suppressor gene, which are often UVB-associated C-->T transition mutations. Clinically, basal cell carcinomas may show a high degree of phenotypical variability. In particular, tumors occurring in atypical locations, showing an unusual clinical appearance, or imitating other skin diseases may cause diagnostic problems. This review article summarizes the current state of the art concerning the etiology, predisposition and molecular genetics of basal cell carcinoma. In addition, examples of unusual clinical manifestations are illustrated.

Congenital linear unilateral basal cell nevus: a case report with patched gene molecular studies

Linear unilateral basal cell nevus represents a linear collection of macules and papules histologically similar to basal cell carcinoma but with benign clinical behavior. We describe a patient who initially presented at the age of 6 months with a unilateral linear basal cell nevus on the right flank. The differential diagnosis included the nevoid basal cell carcinoma syndrome. Constitutional PTCH mutations are causative of the nevoid basal cell carcinoma syndrome, and somatic PTCH mutations are found in the vast majority of basal cell carcinomas. Somatic SMO mutations have also been found in some basal cell carcinomas. Histologic examination of the lesions is performed. Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed. Histologic examination revealed features initially indistinguishable from basal cell carcinoma. Short tandem-repeat DNA analysis did not reveal loss of heterozygosity at the PTCH locus. DNA sequencing of both the PTCH and the SMO genes from the patient's lesions revealed neither inactivating mutations of PTCH nor activating mutations of SMO. Molecular examination indicates that the PTCH and SMO genes are not involved in the pathogenesis of the patients' congenital linear unilateral basal cell nevus. Furthermore, we discuss the relationship between linear basal cell nevus and basaloid follicular hamartoma.

Constitutive activation of the shh–ptc1 pathway by a patched1 mutation identified in BCC

Mutations in the transmembrane receptor patched1 (ptc1) are responsible for the majority of basal cell carcinoma (BCC) cases. Many of these mutations, including ptc1-Q688X, result in premature truncation of the ptc1 protein. ptc1-Q688X has been identified in patients with both BCC and nevoid basal cell carcinoma syndrome, an inheritable disorder causing a predisposition to cancer susceptibility. Here we describe a mechanism by which ptc1-Q688X causes constitutive cellular signaling. Cells expressing ptc1-Q688X demonstrate an increase in cell cycle progression and induce cell transformation. The ptc1-Q688X mutant enhances Gli1 activity, a downstream reporter of sonic hedgehog (shh)-ptc1 signaling, independent of shh stimulation. In contrast to wild-type ptc1, ptc1-Q688X fails to associate with endogenous cyclin B1. Expression of nuclear-targeted cyclin B1 derivatives promotes Gli1-dependent transcription, which correlates temporally with cyclin B1-cdk1 kinase activity. Coexpression of wild-type ptc1 with a nuclear-targeted cyclin B1 derivative, mutated to mimic constitutive phosphorylation, dramatically decreases Gli1 activity. In addition, the coexpression of this constitutively nuclear cyclin B1 derivative with ptc1-Q688X substantially enhances foci formation. These studies therefore describe a molecular mechanism for the aberrant activity of ptc1-Q688X that includes the premature activation of the transcription factor Gli1.

4. Treatment of Non-Melanoma Skin Cancer: Immunotherapy as a Viable Option

Non-melanoma skin cancer (NMSC) is generally considered to be a worldwide epidemic. Current estimates predict that between 0.9 and 1.2 million new cases will be diagnosed each year in the United States of America (USA), which is one-third of all cancers diagnosed (1). In Australia, the incidence of NMSC continues to rise and it now affects at least 1% to 2% of the population annually (1, 2). NMSC tends to affect Caucasians particularly in areas exposed to sunlight, such as the head, neck and back of the hands. There is an increased risk with fair skin, blue eyes and a history of repeated sunburns (1). There are two main forms of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which account for 80% and 16% respectively (1). The majority of BCCs present as two varieties. Nodular BCC (nBCC) appears mostly on the head and neck and accounts for approximately 60% of all BCCs (3). Most of the remainder are superficial BCC (sBCC), which occur on the trunk and extremities (4, 5). Standard treatments for BCCs include excision, curettage and electrodesiccation, and cryosurgery (6). Other forms of treatment such as Mohs micrographic surgery, intralesional interferon (7) and radiotherapy, may be used depending on the nature, site and size of the tumor (6). Actinic keratosis (AK) is considered by some to be the earliest clinically recognizable manifestation of SCC in situ (8, 9). The risk of progression of AK to invasive SCC has been reported as ranging from 0.25 to 20% within 10 – 25 years (8, 10, 11). Sun avoidance measures and sunscreen protection are the first steps in the therapy of AK. The conventional approaches for treating AKs include cryotherapy, electrodesiccation and curettage, excision, CO2 laser therapy, 5-fluorouracil (5-FU), chemical peels and photodynamic therapy (12). Recently, topical immunotherapy in the form of imiquimod 5% cream has demonstrated efficacy for the treatment of BCC and AK. Imiquimod, an immune response modifier, has demonstrated in pre-clinical studies to have both antiviral and antitumor activity in vivo (13). It is currently recommended for the treatment of external genital warts induced by human papillomavirus (14 – 16). This paper reviews the evidence of the safety and efficacy of imiquimod for the treatment of BCC and AK. IMIQUIMOD FOR THE TREATMENT OF BASAL CELL CARCINOMA