RESUMO
ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.
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Movimento Celular/fisiologia , Miosina Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/imunologia , Proteínas do Citoesqueleto , Feminino , Humanos , Interleucina-1alfa/metabolismo , Masculino , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Fosforilação , Proteômica , Receptor Cross-Talk/fisiologia , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
Probably, the most important factor for the survival of a melanoma patient is early detection and precise diagnosis. Although in most cases these tasks are readily carried out by pathologists and dermatologists, there are still difficult cases in which no consensus among experts is achieved. To deal with such cases, new methodologies are required. Following this motivation, we explore here the use of lipid imaging mass spectrometry as a complementary tool for the aid in the diagnosis. Thus, 53 samples (15 nevus, 24 primary melanomas, and 14 metastasis) were explored with the aid of a mass spectrometer, using negative polarity. The rich lipid fingerprint obtained from the samples allowed us to set up an artificial intelligence-based classification model that achieved 100% of specificity and precision both in training and validation data sets. A deeper analysis of the image data shows that the technique reports important information on the tumor microenvironment that may give invaluable insights in the prognosis of the lesion, with the correct interpretation.
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Melanoma , Nevo , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Inteligência Artificial , Nevo/diagnóstico , Nevo/patologia , Lipídeos , Microambiente TumoralRESUMO
BRAF/V600E mutation and other cell growth/growth-control mechanisms are involved in naevogenesis and melanomagenesis. Immunoexpression of BRAF/V600E and other molecules (p16, phosphatase and tensin homologue (PTEN), Ki67, hTERT and Cav3.1 and 3.2 calcium channels) were investigated in 80 histopatho-logically and dermoscopically classified acquired naevi. Regarding BRAF/V600E, dysplastic naevi showed lower immunostaining than common naevi, which was significant in comparison with intradermal naevi, which showed the highest BRAF/V600E histoscore. Junctional naevi showed the lowest BRAF/V600E levels. Globular/cobblestone and reticular dermoscopic patterns were consistently associated with high and low BRAF/V600E immunoexpression, respectively, but Zalaudek's peripheral globule pattern (CR/PG) showed the highest BRAF/V600E immunoexpression. Among global patterns, the previously not investigated multicomponent pattern showed the lowest BRAF/V600E immunoexpression. Regarding the remaining biomarkers, new immunohistochemical features were found, in particular p16 and PTEN low expression in multicomponent pattern; and Ki67, hTERT and Cav.3.1 high expression in CR/PG. In conclusion, histopathology and dermoscopy provide complementary information regarding the biology of melanocytic naevi.
Assuntos
Canais de Cálcio Tipo T , Nevo Pigmentado , Neoplasias Cutâneas , Biomarcadores , Dermoscopia , Humanos , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma of mature cytotoxic T cells. Initially, patients with SPTCL were treated with doxorubicin-based polychemotherapy. OBJECTIVE: To analyze clinical, biologic, immunophenotypical, molecular, imaging, treatment, and outcome data reflecting the current state of knowledge. METHODS: A retrospective multicenter study of 16 patients with SPTCL that was diagnosed between 1996 and 2016. RESULTS: The female-to-male ratio was 1.7. The median age at diagnosis was 46.5 years. Patients presented with multiple nodular or plaque-like lesions preferentially affecting the legs and/or trunk. Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3+, CD4-, CD8+, CD56-, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate. SPTCL was associated with autoimmune diseases in 25% of patients, and with the development of hemophagocytic syndrome in 18% of patients. Oral steroids alone or in combination with low-dose methotrexate or cyclosporine A were the most common initial treatment, achieving a complete response in 85% of the treated patients. The median follow-up time was 14 months. The 5-year disease-specific survival rate was 85.7%. LIMITATIONS: This was a retrospective study. CONCLUSIONS: SPTCL has an excellent prognosis. Immunosuppressive agents can be considered for first-line treatment.
Assuntos
Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/terapia , Linfoma de Células T/patologia , Linfoma de Células T/terapia , Paniculite/patologia , Paniculite/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Quimiorradioterapia/métodos , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/mortalidade , Linfoma Cutâneo de Células T/diagnóstico por imagem , Linfoma Cutâneo de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Paniculite/diagnóstico por imagem , Paniculite/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/mortalidade , Espanha , Análise de Sobrevida , Adulto JovemRESUMO
This study aims to assess ligament lesions and subluxations of the carpometacarpal (CMC) joint of the thumbs and the role that these ligament ruptures play in the pathophysiology of osteoarthritis (OA). Twenty-five fresh-frozen cadaver hands were dissected. There were 14 female and 11 male with mean age 65 years (51-92 years old). The origin, insertion, and fibre orientation of the ligaments were identified based on Berger´s anatomical descriptions. Length, thickness and width of the main ligaments were measured. The ligament ruptures and the metacarpal translation associated with these ruptures were measured (mm). Cartilage thickness in the trapezium and metacarpal of specimens was assessed. We investigated the relationship between the ligament ruptures and the area of chondromalacia and OA. In the specimens that showed an isolated or combined rupture in DRL we found a significant increase in the dorsal translation of metacarpal with a mean of 1.7 mm. Statistical analysis of data demonstrates a significant difference (P = 0.006). There was a relationship between the presence of a tear in the DRL and OA in the radial quadrants (P = 0.032). These observations suggest a translation of metacarpal on trapezium in the production of arthritic lesions and support a hypothesis that pathologic joint instability could be a cause of CMC osteoarthritis. This study suggests that repairing the DRL during ligament reconstruction of the CMC joint should be considered.
Assuntos
Luxações Articulares/complicações , Ligamentos Articulares/lesões , Ligamentos Articulares/patologia , Osteoartrite/etiologia , Ruptura/complicações , Idoso , Idoso de 80 Anos ou mais , Cadáver , Articulações Carpometacarpais , Doenças das Cartilagens/complicações , Doenças das Cartilagens/patologia , Cartilagem Articular/patologia , Dissecação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PolegarRESUMO
The worldwide incidence of malignant melanoma is increasing. The number of pigmented naevi and amount of solar exposure are important risk factors. The aim of this study was to characterize a paediatric population (from Lleida, Catalonia, Spain) in terms of phenotype, sun behaviour and naevi prevalence. Data on the numbers and distributions of acquired naevi in 369 children, aged 4, 8 and 14 years, were collected and correlated with age, sex, skin phototype and environmental factors (annual/lifetime intermittent and chronic sun exposure, sunburns and sunscreen use). The density of naevi increased with age. Boys had more naevi on the trunk and girls had more naevi on the legs. Children with light skin phototype had more naevi. A higher level of accumulated sun exposure correlated with a higher number of naevi in children with non-adequate sunscreen use. In conclusion, several risk factors associated with naevi density and distribution were found, as previously reported by others. Multivariate analysis confirmed a protective role of sunscreen in the development of acquired melanocytic naevi.
Assuntos
Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/prevenção & controle , Nevo Pigmentado/epidemiologia , Nevo Pigmentado/prevenção & controle , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Luz Solar/efeitos adversos , Protetores Solares/uso terapêutico , Adolescente , Fatores Etários , Distribuição de Qui-Quadrado , Criança , Estudos Transversais , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Análise Multivariada , Neoplasias Induzidas por Radiação/diagnóstico , Nevo Pigmentado/diagnóstico , Razão de Chances , Prevalência , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Pigmentação da Pele , Espanha/epidemiologia , Fatores de TempoRESUMO
All cases of MM diagnosed in 23 hospitals in Catalonia, from 2000 to 2007 were recorded and melanoma incidence calculated and adjusted for the European standard population via the direct method. The age standardised rate/100,000 inhabitants varied from 6.74 in 2000 to 8.64 in 2007 for all melanomas and from 4.79 to 5.80 for invasive MMs; the Breslow thickness was stable during the period. The increase in invasive melanoma incidence in the elderly was remarkable, the crude rate/100,000 inhabitants increasing from 11.04 (2000) to 15.49 (2007) in the 60-64 year population, while remaining more stable in the 30-34 year range, from 3.97 in 2000 to 4.55 in 2007, and with a tendency to decrease from 5.1 in 2000 to 2.5 in 2007 for the age range of 25-29 years. These lower age ranges are much more affected by immigration. Despite the large immigrant population (nearly one million immigrants arrived in Catalonia during the study period from countries with a low melanoma incidence), melanoma incidence in our region has risen considerably and this trend is likely to persist in the near future.
Assuntos
Melanoma/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Distribuição por Idade , Idoso , Emigração e Imigração , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espanha/epidemiologia , Adulto JovemRESUMO
A 62-year-old woman with a past medical history of rheumatoid arthritis was referred to the Department of Dermatology because of an enlarging cutaneous lesion on the right thumb which resembled a soft tissue infection. She had received antibiotics without significant improvement. Clinical examination revealed an erythematous nodule involving almost the whole surface of the distal phalanx with spontaneous drainage of countless of small yellowish ovoid granules. Histopathologic study of these structures showed an inner core of amorphous acidophilic material with some interspersed chronic inflammatory cells and a surrounding thin fibrin layer. Special stains and cultures were negative for parasites, bacterium and mycobacterium. Magnetic resonance imaging (MRI) revealed distension of the first and fifth finger flexor sheaths and common finger flexor sheath. These areas were filled by fluid and multiple small nodular lesions. A diagnosis of non-infectious rice body tenosynovitis was rendered and surgical removal was performed. Total recovery was observed with no evidence of recurrence after 6 months of follow-up. To our knowledge, this is the first report of rice body tenosynovitis presenting as a pseudoinflammatory cutaneous lesion with evolution to a cutaneous fistula with drainage of rice grain-like structures. The description of this impressive and peculiar clinical and histopathologic picture is important to further recognize similar cases.
Assuntos
Abscesso/patologia , Dermatopatias/patologia , Pele/patologia , Tenossinovite/patologia , Abscesso/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Dermatopatias/cirurgia , Tenossinovite/cirurgiaRESUMO
Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the nucleus must be tuned since they pose a challenge to the negotiation of physical constraints imposed by the microenvironment and tissue structure. We discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells, at the invasive front of human primary melanoma tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. Here, using in vitro and in vivo models that recapitulate human melanoma progression, we found that expression of the shorter isoform, LAP1C, supports nuclear envelope blebbing, constrained migration and invasion by allowing a weaker coupling between the nuclear envelope and the nuclear lamina. We propose that LAP1 renders the nucleus highly adaptable and contributes to melanoma aggressiveness.
Assuntos
Melanoma , Membrana Nuclear , Humanos , Isoformas de Proteínas/metabolismo , Movimento Celular , Membrana Nuclear/metabolismo , Melanoma/genética , Melanoma/metabolismo , Microambiente TumoralRESUMO
We aimed to characterise cutaneous melanoma in the elderly and determine its association with poorer prognosis. We studied a prospective cohort of the melanoma population in Catalonia between 2012 and 2016. We compared young patient group (<75 years old) with elderly patient group (≥75 years old). We included 3009 patients (52.5% women) from 14 centres, with a mean age at diagnosis of 61.1 years. In the ≥75-year-old group there was a predominance of men (53.9% vs. 45.5%, P â <â 0.001), melanoma was more frequently located in the head and neck area (37.7% vs. 15.5%, P â <â 0.001) and lentigo maligna melanoma subtype was significantly more frequent (31.4% vs. 11.6%, P â <â 0.001), as were nodular melanoma and acral lentiginous melanoma ( P â <â 0.001). In older people, Breslow index, the presence of ulceration and mitotic rate were higher than in younger people. Kaplan-Meier survival curves showed longer melanoma-specific survival (MSS) and melanoma-free survival (MFS) in <75-year-old group compared to the elderly group. Cox regression models demonstrated reduced MSS in patients ≥75 years regardless of gender, location, IB, ulceration and lymph node status at diagnosis (HR 1.54, P â =â 0.013) whereas MFS was not independently associated with elderly when head and neck location was considered. Age appears to be an independent risk factor for MSS but not for MFS. Worse melanoma prognosis in elderly could be explained by factors unrelated to the tumour, such as age-related frailty and comorbidities that limit the access to systemic treatments and, eventually, age-related immune dysfunction.
Assuntos
Melanoma , Neoplasias Cutâneas , Masculino , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Melanoma/patologia , Neoplasias Cutâneas/patologia , Estudos Prospectivos , Estudos de Coortes , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Biópsia de Linfonodo Sentinela , Melanoma Maligno CutâneoRESUMO
Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.
Assuntos
Proteínas Quinases Ativadas por AMP , Dinâmica Mitocondrial , Neoplasias , Humanos , Trifosfato de Adenosina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Adesão Celular , Movimento Celular/fisiologia , Miosina Tipo II/metabolismo , Fosforilação Oxidativa , FosforilaçãoRESUMO
Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral-mediated short-hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib-induced growth arrest in Sunitinib-sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho-Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Indóis/farmacologia , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Bortezomib , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Humanos , Melanoma/patologia , Morfolinas/farmacologia , RNA Interferente Pequeno/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: Approximately 4% of cutaneous squamous cell carcinomas (cSCCs) develop lymphatic metastases. The value of lymphatic endothelial markers to enhance the detection of lymphatic tumor invasion in cSCC has not been assessed previously. OBJECTIVE: We sought to evaluate the use of the antibody D2-40, a podoplanin immunohistochemical marker, to identify tumor lymph vessel invasion in cSCC and to assess its expression in tumor cells. METHODS: This was a retrospective case-control study. A series of 101 cSCC, including 51 cases that developed lymphatic metastatic spread (metastasizing cSCC [MSCC]) and 50 cases that resolved definitely after surgical excision (non-MSCC) were included in the study. Lymph vessel invasion using D2-40 was evaluated on all primary biopsy specimens. The percentage of tumor cells showing D2-40 positivity and intensity scoring were recorded. All the immunohistochemical findings were correlated with the clinicopathological features. RESULTS: Lymph vessel invasion was observed in 8% of non-MSCCs and in 25.5% of MSCCs (P = .031). D2-40 expression was significantly increased, both in intensity (odds ratio 4.42 for intensity ++/+++) and in area (odds ratio 2.29 for area >10%), in MSCC when compared with non-MSCC. Interestingly, almost half (49%) of the MSCC had moderate to intense D2-40 positivity compared with 16% of non-MSCC. D2-40 immunohistochemical expression was increased in tumors with an infiltrative pattern of extension. In the multivariate analysis, histologically poorly differentiated tumors, recurrent lesions, and cSCC showing D2-40 overexpression (in intensity) were significantly associated with lymphatic metastases development (odds ratios 15.67, 14.72, and 6.07, respectively). LIMITATIONS: This was a retrospective study. CONCLUSION: The expression of podoplanin associates with high metastatic risk in cSCC.
Assuntos
Anticorpos Monoclonais Murinos/biossíntese , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Idoso , Anticorpos Monoclonais Murinos/análise , Biomarcadores/análise , Carcinoma de Células Escamosas/química , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Estudos Retrospectivos , Medição de Risco , Neoplasias Cutâneas/químicaRESUMO
Cutaneous melanoma is the most aggressive of skin tumors. In order to discover new biomarkers that could help us improve prognostic prediction in melanoma patients, we have searched for germline DNA variants associated with melanoma progression. Thus, after exome sequencing of a set of melanoma patients and healthy control individuals, we identified rs1042602, an SNP within TYR, as a good candidate. After genotyping rs1042602 in 1025 patients and 773 healthy donors, we found that the rs1042602-A allele was significantly associated with susceptibility to melanoma (CATT test: p = 0.0035). Interestingly, we also observed significant differences between patients with good and bad prognosis (5 years of follow-up) (n = 664) (CATT test for all samples p = 0.0384 and for men alone p = 0.0054). Disease-free-survival (DFS) analyses also showed that patients with the A allele had shorter DFS periods. In men, the association remained significant even in a multivariate Cox Proportional-hazards model, which was adjusted for age at diagnosis, Breslow thickness, ulceration and melanoma subtype (HR 0.4; 95% confidence interval (CI) 0.20-0.83; p = 0.0139). Based on our results, we propose that rs1042602-A is a risk allele for melanoma, which also seems to be responsible for a poorer prognosis of the disease, particularly in men.
RESUMO
BACKGROUND: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. METHODS: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. RESULTS: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. CONCLUSIONS: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.
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T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.
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Real-world data on BRAF mutation frequency in advanced melanoma are lacking in Spain. Moreover, data available on clinicopathological profile of patients with advanced BRAF-mutant melanoma are currently limited. This study aimed to assess the frequency of BRAF V600 mutations in Spanish patients with advanced or metastatic melanoma and to identify clinical and histopathological features associated with BRAF-mutated tumors. A multicenter, cross-sectional epidemiological study was conducted in 33 Spanish hospitals in adult patients with stage IIIc/IV melanoma. A total of 264 patients were included. The median age was 68â¯years and 57% were male. Melanoma mainly involved skin with intermittent (40.4%) and low or no sun exposure (43.5%). Most patients (85.6%) had stage IV disease (M1a: 19.3%; M1b: 13.3%; M1c: 22.7%). Serum lactate dehydrogenase levels were elevated in 20% of patients. Superficial spreading melanoma was the most frequent histological type (29.9%). Samples were predominantly obtained from metastases (62.7%), mostly from skin and soft tissues (80%). BRAF mutation analysis was primarily performed using the Cobas 4800 BRAF V600 Mutation Test (92.8%) on formalin-fixed, paraffin-embedded tissue (95.8%). BRAF mutations were detected in 41.3% of samples. Multivariate analysis identified age (odd ratio [OR] 0.975) and stage IV M1a (OR 2.716) as independent factors associated with BRAF mutation. The frequency of BRAF mutations in tumor samples from patients with advanced or metastatic melanoma in Spain was 41.3%. BRAF mutations seem to be more frequent in younger patients and stage M1a patients. This study provides the basis for further investigation regarding BRAF-mutated advanced melanoma in larger cohorts.
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Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAFV600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates because of autophagy blockade only in BRAFV600E-mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAFV600E-mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration and invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAFV600E-mutant melanoma and a therapeutic strategy to reduce progression toward BRAF inhibitor resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
Assuntos
Receptores Frizzled/metabolismo , Melanoma/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Wnt/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Transformação Celular Neoplásica , Feminino , Receptores Frizzled/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos SCID , Proteínas dos Microfilamentos/genética , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Invasividade Neoplásica , Transdução de Sinais , Proteínas Wnt/genética , Proteínas rho de Ligação ao GTP/genética , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
The incidence of melanoma has been increasing worldwide during recent decades. The objective of the study was to analyse the trends in incidence for in situ and invasive melanoma in the Spanish region of Catalonia during the period of 2008-2017. We designed a cross-sectional study with an age-period-cohort analysis of melanoma patient data from the Network of Melanoma Centres in Catalonia. Our database covered a population of over seven million and included a total of 8626 patients with incident melanoma. The main outcome measures were crude and age-standardised incidence rates to the European 2013 standard population. Joinpoint regression models were used to evaluate the population trends. We observed an increase in the age-standardised incidence rate (per 100,000 population) of all melanoma subtypes from 11.56 in 2008 to 13.78 in 2017 with an average annual percent change (AAPC) of 3.5%. This incidence increase was seen exclusively in the older population. Moreover, the stratified analysis showed a statistically significant increase in the age-standardised incidence rate for invasive (AAPC 2.1%) and in situ melanoma (AAPC 6.5%). In conclusion, the incidence of melanoma has continued to increase in the elderly population over recent decades, with a rapidly increasing trend of in situ melanomas and the lentigo maligna subtype.