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Cell Jul 2020To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and...
To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Multiple features of potential immunosuppression were observed, including T regulatory cell (Treg) co-localization with CD8 T cells in compartmentalized tumor stroma. Finally, single-cell characterization of human tumor xenografts and in vivo CRISPR screens identified essential roles for specific tumor subpopulation-enriched gene networks in tumorigenesis. These data define cSCC tumor and stromal cell subpopulations, the spatial niches where they interact, and the communicating gene networks that they engage in cancer.
Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Clustered Regularly Interspaced Short Palindromic Repeats; Genomics; Humans; Keratinocytes; Mice; RNA-Seq; Single-Cell Analysis; Skin; Skin Neoplasms; Transcriptome; Transplantation, Heterologous
PubMed: 32579974
DOI: 10.1016/j.cell.2020.05.039 -
Acta Dermato-venereologica Jun 2020Basal cell carcinomas are the most frequent skin cancers in the fair-skinned adult population over 50 years of age. Their incidence is increasing throughout the world.... (Review)
Review
Basal cell carcinomas are the most frequent skin cancers in the fair-skinned adult population over 50 years of age. Their incidence is increasing throughout the world. Ultraviolet (UV) exposure is the major carcinogenic factor. Some genodermatosis can predispose to formation of basal cell carcinomas at an earlier age. Basal cell carcinomas are heterogeneous, from superficial or nodular lesions of good prognosis to very extensive difficult-to-treat lesions that must be discussed in multidisciplinary committees. Recent guidelines have updated the management of basal cell carcinoma. The prognosis is linked to the risk of recurrence of basal cell carcinoma or its local destructive capacity. Characteristic molecular events in these tumours are: (i) activation of the hedgehog pathway, which has allowed the development of hedgehog inhibitors for difficult-to-treat lesions that are not accessible to surgery or radiotherapy; (ii) high mutational burden, which suggests that hedgehog inhibitor refractory tumours could be offered immunotherapy; some trials are ongoing. The standard treatment for most basal cell carcinomas is surgery, as it allows excision margin control and shows a low risk of recurrence. Superficial lesions can be treated by non-surgical methods with significant efficacy.
Topics: Biomarkers, Tumor; Carcinoma, Basal Cell; Dermatologic Surgical Procedures; Genetic Predisposition to Disease; Humans; Immunotherapy; Molecular Targeted Therapy; Mutation; Phenotype; Skin Neoplasms; Treatment Outcome
PubMed: 32346750
DOI: 10.2340/00015555-3495 -
The Journal of Investigative Dermatology Apr 2021UVR is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In the skin, TGFβ signaling is a growth inhibitor for... (Review)
Review
UVR is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In the skin, TGFβ signaling is a growth inhibitor for keratinocytes and a profibrotic factor in the dermis. It exerts context-dependent effects on tumor progression. Chronic UV exposure likely causes TGFβ1/SMAD3 signaling activation and contributes to metalloproteinase-induced collagen degradation and photoinflammation in photoaging. UV irradiation also causes gene mutations in key elements of the TGFβ pathway, including TGFβRI, TGFβRII, SMAD2, and SMAD4. These mutations enable tumor cells to escape from TGFβ-induced growth inhibition and induce genomic instability and cancer stem cells, leading to the initiation, progression, invasion, and metastasis of cutaneous squamous cell carcinoma (cSCC). Furthermore, UV-induced mutations cause TGFβ overexpression in the tumor microenvironment (TME) of cSCC, basal cell carcinoma (BCC), and cutaneous melanoma, resulting in inflammation, angiogenesis, cancer-associated fibroblasts, and immune inhibition, supporting cancer survival, immune evasion, and metastasis. The pleiotropic effects of TGFβ provide possible treatment options for photoaging and skin cancer. Given the high UV-induced mutational burden and immune-repressive TME seen in cSCC, BCC, and cutaneous melanoma, treatment with the combination of a TGFβ signaling inhibitor and immune checkpoint blockade could reverse immune evasion to reduce tumor growth.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Genomic Instability; Humans; Immune Checkpoint Inhibitors; Keratinocytes; Mice; Mutation; Signal Transduction; Skin; Skin Aging; Skin Neoplasms; Transforming Growth Factor beta; Tumor Escape; Tumor Microenvironment; Ultraviolet Rays; Xenograft Model Antitumor Assays
PubMed: 33358021
DOI: 10.1016/j.jid.2020.11.007 -
American Family Physician Sep 2020Keratinocyte carcinoma, traditionally referred to as nonmelanoma skin cancer, includes basal cell and cutaneous squamous cell carcinoma and is the most common skin... (Review)
Review
Keratinocyte carcinoma, traditionally referred to as nonmelanoma skin cancer, includes basal cell and cutaneous squamous cell carcinoma and is the most common skin cancer malignancy found in humans. The U.S. Preventive Services Task Force recommends counseling about minimizing exposure to ultraviolet radiation for people aged six months to 24 years with fair skin types to decrease their risk of skin cancer. Routine screening for skin cancer is controversial. The U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of a routine whole-body skin examination to screen for skin cancer. Basal cell carcinoma commonly appears as a shiny, pearly papule with a smooth surface, rolled borders, and arborizing telangiectatic surface vessels. Cutaneous squamous cell carcinoma commonly appears as a firm, smooth, or hyperkeratotic papule or plaque, and may have central ulceration. Initial tissue sampling for diagnosis is a shave technique if the lesion is raised, or a punch biopsy of the most abnormal-appearing area of skin. High-risk factors for recurrence and metastasis include prior tumors, ill-defined borders, aggressive histologic patterns, and perineural invasion. Mohs micrographic surgery has the lowest recurrence rate among treatments but is best considered for large, high-risk tumors or tumors in sensitive anatomic locations. Smaller, lower-risk tumors are treated with surgical excision, electrodesiccation and curettage, or cryotherapy. Topical imiquimod and fluorouracil are also treatment options for superficial basal cell carcinoma and squamous cell carcinoma in situ. There are no clear guidelines for follow up after an index keratinocyte carcinoma, but monitoring for recurrence is important because the five-year risk of subsequent skin cancer is 41%. After more than one diagnosis, the five-year risk increases to 82%.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Family Practice; Humans; Mohs Surgery; Practice Patterns, Physicians'; Skin Neoplasms
PubMed: 32931212
DOI: No ID Found -
International Journal of Dermatology Jun 2020Actinic keratosis (AK) is a very common skin disease caused by chronic sun damage, which in 75% of cases arises on chronically sun-exposed areas, such as face, scalp,... (Review)
Review
Actinic keratosis (AK) is a very common skin disease caused by chronic sun damage, which in 75% of cases arises on chronically sun-exposed areas, such as face, scalp, neck, hands, and forearms. AKs must be considered an early squamous cell carcinoma (SCC) for their probable progression into invasive SCC. For this reason, all AK should be treated, and clinical follow-up is recommended. The aims of treatment are: (i) to clinically eradicate evident and subclinical lesions, (ii) to prevent their evolution into SCC, and (iii) to reduce the number of relapses. Among available treatments, it is possible to distinguish lesion-directed therapies and field-directed therapies. Lesion-directed treatments include: (i) cryotherapy; (ii) laser therapy; (iii) surgery; and (iv) curettage. Whereas, field-directed treatments are: (i) 5-fluorouracil (5-FU); (ii) diclofenac 3% gel; (iii) chemical peeling; (iv) imiquimod; and (v) photodynamic therapy (PDT). Prevention plays an important role in the treatment of AKs, and it is based on the continuous use of sunscreen and protective clothing. This review shows different types of available treatments and describes the characteristics and benefits of each medication, underlining the best choice.
Topics: Aftercare; Carcinoma, Squamous Cell; Chemexfoliation; Cryotherapy; Curettage; Dermoscopy; Diclofenac; Disease Progression; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Laser Therapy; Photochemotherapy; Practice Guidelines as Topic; Protective Clothing; Skin; Skin Neoplasms; Sunlight; Sunscreening Agents
PubMed: 32012240
DOI: 10.1111/ijd.14767 -
International Journal of Molecular... Mar 2022Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell... (Review)
Review
Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Incidence; Skin Neoplasms; United States
PubMed: 35408839
DOI: 10.3390/ijms23073478 -
Advances in Therapy Jan 2020Skin cancer, including melanoma, basal cell carcinoma and cutaneous squamous cell carcinoma, has one of the highest global incidences of any form of cancer. In 2016 more...
Skin cancer, including melanoma, basal cell carcinoma and cutaneous squamous cell carcinoma, has one of the highest global incidences of any form of cancer. In 2016 more than 16,000 people were diagnosed with melanoma in the UK. Over the last decade the incidence of melanoma has increased by 50% in the UK, and about one in ten melanomas are diagnosed at a late stage. Among the keratinocyte carcinomas (previously known as non-melanoma skin cancers), basal cell carcinoma is the most common cancer amongst Caucasian populations. The main risk factor for all skin cancer is exposure to ultraviolet radiation-more than 80% are considered preventable. Primary care clinicians have a vital role to play in detecting and managing patients with skin lesions suspected to be skin cancer, as timely diagnosis and treatment can improve patient outcomes, particularly for melanoma. However, detecting skin cancer can be challenging, as common non-malignant skin lesions such as seborrhoeic keratoses share features with less common skin cancers. Given that more than 80% of skin cancers are attributed to ultraviolet (UV) exposure, primary care clinicians can also play an important role in skin cancer prevention. This article is one of a series discussing cancer prevention and detection in primary care. Here we focus on the most common types of skin cancer: melanoma, squamous cell carcinoma and basal cell carcinoma. We describe the main risk factors and prevention advice. We summarise key guidance on the symptoms and signs of skin cancers and their management, including their initial assessment and referral. In addition, we review emerging technologies and diagnostic aids which may become available for use in primary care in the near future, to aid the triage of suspicious skin lesions.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Melanoma; Physical Examination; Primary Health Care; Sensitivity and Specificity; Skin Neoplasms; Ultraviolet Rays
PubMed: 31734824
DOI: 10.1007/s12325-019-01130-1 -
International Journal of Molecular... Oct 2022Retinoids are natural and synthetic vitamin A derivatives that are effective for the prevention and the treatment of non-melanoma skin cancers (NMSC). NMSCs constitute a... (Review)
Review
Retinoids are natural and synthetic vitamin A derivatives that are effective for the prevention and the treatment of non-melanoma skin cancers (NMSC). NMSCs constitute a heterogenous group of non-melanocyte-derived skin cancers that impose substantial burdens on patients and healthcare systems. They include entities such as basal cell carcinoma and cutaneous squamous cell carcinoma (collectively called keratinocyte carcinomas), cutaneous lymphomas and Kaposi's sarcoma among others. The retinoid signaling pathway plays influential roles in skin physiology and pathology. These compounds regulate diverse biological processes within the skin, including proliferation, differentiation, angiogenesis and immune regulation. Collectively, retinoids can suppress skin carcinogenesis. Both topical and systemic retinoids have been investigated in clinical trials as NMSC prophylactics and treatments. Desirable efficacy and tolerability in clinical trials have prompted health regulatory bodies to approve the use of retinoids for NMSC management. Acceptable off-label uses of these compounds as drugs for skin cancers are also described. This review is a comprehensive outline on the biochemistry of retinoids, their activities in the skin, their effects on cancer cells and their adoption in clinical practice.
Topics: Humans; Skin Neoplasms; Retinoids; Carcinoma, Squamous Cell; Vitamin A; Carcinoma, Basal Cell
PubMed: 36293471
DOI: 10.3390/ijms232012622 -
European Journal of Cancer (Oxford,... Mar 2020In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a...
In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics.
Topics: Aftercare; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Carcinoma, Squamous Cell; Chemoradiotherapy; Clinical Decision-Making; Consensus; Dermatologic Surgical Procedures; Dermatology; Humans; Lymph Node Excision; Lymph Nodes; Margins of Excision; Medical Oncology; Neoplasm Staging; Palliative Care; Patient Care Team; Patient Education as Topic; Skin; Skin Neoplasms; Societies, Medical; Sunlight
PubMed: 32113942
DOI: 10.1016/j.ejca.2020.01.008 -
Anais Brasileiros de Dermatologia 2021Mohs micrographic surgery is a specialized form of skin cancer surgery that has the highest cure rates for several cutaneous malignancies. Certain skin cancers can have... (Review)
Review
Mohs micrographic surgery is a specialized form of skin cancer surgery that has the highest cure rates for several cutaneous malignancies. Certain skin cancers can have small extensions or "roots" that may be missed if an excised tumor is serially cross-sectioned in a "bread-loaf" fashion, commonly performed on excision specimens. The method of Mohs micrographic surgery is unique in that the dermatologist (Mohs surgeon) acts as both surgeon and pathologist, from the preoperative considerations until the reconstruction. Since Dr. Mohs's initial work in the 1930s, the practice of Mohs micrographic surgery has become increasingly widespread among the dermatologic surgery community worldwide and is considered the treatment of choice for many common and uncommon cutaneous neoplasms. Mohs micrographic surgery spares the maximal amount of normal tissue and is a safe procedure with very few complications, most of them managed by Mohs surgeons in their offices. Mohs micrographic surgery is the standard of care for high risks basal cell carcinomas and cutaneous squamous cell carcinoma and is commonly and increasingly used for melanoma and other rare tumors with superior cure rates. This review better familiarizes the dermatologists with the technique, explains the difference between Mohs micrographic surgery and wide local excision, and discusses its main indications.
Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Melanoma; Mohs Surgery; Skin Neoplasms
PubMed: 33849752
DOI: 10.1016/j.abd.2020.10.004