The regulation and function of collagenase-3 (MMP-13) in cutaneous wound healing and squamous cell carcinoma

Matrix metalloproteinase-13 (MMP-13) is a potent proteolytic enzyme, whose expression has been previously associated with fetal bone development and postnatal bone remodeling and with adult gingival wound healing. MMP-13 is also known to be involved in the growth and invasion of various cancers including squamous cell carcinoma (SCC) of the skin. The aim of this study was to further elucidate the function and regulation of MMP-13 in wound repair and cancer. In this study, it was shown that fetal skin fibroblasts express MMP-13 in response to transforming growth factor-β in a p38 MAP kinase dependent manner. In addition, MMP-13 was found to be expressed in vivo by wound fibroblasts in human fetal skin grafted on SCID mice. Adenovirally delivered expression of MMP-13 enhanced collagen matrix contraction by fibroblasts in vitro in association with altered cytoskeletal structure, enhanced proliferation and survival. These results indicate that MMP-13 is involved in cell-mediated collagen matrix remodeling and suggest a role for MMP-13 in superior matrix remodeling and scarless healing of fetal skin wounds. Using an MMP-13 deficient mouse strain, it was shown that MMP-13 is essential for the normal development of experimental granulation tissue in mice. MMP-13 was implicated in the regulation of myofibroblast function and angiogenesis and the expression of genes involved in cellular proliferation and movement, immune response, angiogenesis and proteolysis. Finally, epidermal mitogen, keratinocyte growth factor (KGF) was shown to suppress the malignant properties of skin SCC cells by downregulating the expression of several target genes with potential cancer promoting properties, including MMP-13, and by reducing SCC cell invasion. These results provide evidence that MMP-13 potently regulates cell viability, myofibroblast function and angiogenesis associated with wound healing and cancer. In addition, fibroblasts expressing MMP-13 show high collagen reorganization capacity. Moreover, the results suggest that KGF mediates the anti-cancer effects on skin SCC

Carcinoma de células de Merkel em extremidade inferior

Merkel Cells Carcinoma is a rare cutaneous neoplasia. Studies revealed an increase in the occurrence from 0.15 to 0.44 cases for every 100.000 inhabitants between 1986 and 2001. Around 50% of the patients, eventually, develop systemic disease, being the most common sites the liver, the bones and the brain. The etiology is still unknown. The present study presents a new case of Merkel cells carcinoma in extremity, treated with local resection and adjuvant radiotherapy.

Transitional cell carcinoma of urinary bladder with metastasis in lumbar vertebrae and spinal cord compression in an ocelot(Leopardus pardalis)

This paper reports a case of nonpapillary and infiltrative transitional cell carcinoma (TCC) of the urinary bladder with metastasis of lumbar vertebrae and spinal cord compression in an adult female ocelot (Leopardus pardalis), from the Mato Grosso state, Brazil. The ocelot had pelvic limb paralysis and skin ulcers in the posterior region of the body and was submitted to euthanasia procedure. At necropsy was observed a multilobulated and irregular shaped, yellowish to white nodule in the urinary bladder. The nodule had a soft consistency and arised from the mucosa of the urinary bladder extending throughout the muscular layers and the serosa. Nodules of similar appearance infiltrating the vertebral column the at L6 and L7 vertebrae with corresponding spinal canal invasion were also observed. The histological evaluation showed epithelial neoplastic proliferation in the urinary bladder with characteristics of nonpapillary and infiltrative TCC, with positive immunohistochemical staining for pancytokeratin, and strong immunostaining for cytokeratin of low molecular weight, and weak or absent labeling for high molecular weight cytokeratin. This is the first report of TCC of urinary bladder in ocelot in Brazil.

No evidence for mutations in exons 1, 8 and 18 of the patched gene in sporadic skin lesions of Brazilian patients

There is strong evidence that the patched (PTCH) gene is a gene for susceptibility to the nevoid basal cell carcinoma syndrome. PTCH has also been shown to mutate in both familial and sporadic basal cell carcinomas. However, mutations of the gene seem to be rare in squamous cell carcinomas. In order to characterize the role of the gene in the broader spectrum of sporadic skin malignant and pre-malignant lesions, we performed a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis of genomic DNA extracted from 105 adult patients (46 females and 59 males). There were 66 patients with basal cell carcinomas, 30 with squamous cell carcinomas, 2 with malignant melanomas and 7 patients with precancerous lesions. Two tissue samples were collected from each patient, one from the central portion of the tumor and another from normal skin. Using primers that encompass the entire exon 1, exon 8 and exon 18, where most of the mutations have been detected, we were unable to demonstrate any band shift. Three samples suspected to present aberrant migrating bands were excised from the gel and sequenced directly. In addition, we sequenced 12 other cases, including tumors and corresponding normal samples. A wild-type sequence was found in all 15 cases. Although our results do not exclude the presence of clonal alterations of the PTCH gene in skin cancers or mutations in other exons that were not screened, the present data do not support the presence of frequent mutations reported for non-melanoma skin cancer of other populations.

Complement system in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) consists 20% of keratinocytederived non-melanoma skin cancers (NMSC), the incidence of which is increasing globally. cSCC is the most common metastatic skin cancer and it causes approximately 20% of skin cancer-related deaths. At present, there are no molecular markers for predicting which cSCC lesions are aggressive or metastasize rapidly. UV radiation is the most important risk factor for cSCC. During the development of cSCC, normal epidermal keratinocytes are transformed and form actinic keratosis (AK), which progresses to cSCC in situ (cSCCIS, Bowen’s disease) and finally to invasive and metastatic cSCC. Inflammatory factors and cells are a part of cancer microenvironment and cSCC can develop in the chronically irritated skin or in the context of chronic inflammation. The complement system is a central part of innate immunity and it regulates normal immunological and inflammatory processes. In this study, the role of complement system components and inhibitors were studied in the progression of cSCC in culture and in vivo. Elevated expression of complement factor H (CFH), complement factor I (CFI), complement component C3 and complement factor B (CFB) was noted in cSCC cells in culture. The analysis with immunohistochemistry (IHC) revealed that the expression of CFH, CFI, C3 and CFB was specifically noted in tumor cells in vivo. The staining intensity of CFH, CFI, C3 and CFB was also stronger in invasive cSCC than in AK or cSCCIS samples. The knockdown of CFH, CFI and CFB with specific siRNAs decreased cSCC cell viability and migration, whereas the knockdown of C3 reduced only cSCC cell migration. Moreover, the knockdown of CFI, C3 and CFB inhibited growth of cSCC xenograft tumors established in SCID mice in vivo. In these tumors, CFI, C3 and CFB knockdown decreased the number of proliferating cells. Moreover, the knockdown of CFI increased local inflammation and complement activation. This study provides evidence for the roles of CFH, CFI, C3 and CFB in the tumor progression indicating these as molecular biomarkers and putative therapeutic targets of cSCC.

Roles of novel biomarkers in progression of cutaneous squamous cell carcinoma

Roles of novel biomarkers was studied in progression of cutaneous squamous cell carcinoma (cSCC) as the most common metastatic skin cancer. The incidence of cSCC is increasing worldwide due to lifestyle changes such as recreational exposure to sunlight and the aging of the population. Because of an emerging need for molecular markers for the progression of cSCC, we set our goal to characterize three distinct novel markers overexpressed in cSCC cells. Our results identified overexpression of serpin peptidase inhibitor clade A member 1 (SerpinA1), EphB2 and absent in melanoma 2 (AIM2) in cSCC cell lines compared with normal human epidermal keratinocytes (NHEKs). Immunohistochemical analysis of SerpinA1, EphB2 and AIM2 revealed abundant tumor cell-specific expression of cytoplasmic SerpinA1 and AIM2 and cytoplasmic and membranous EphB2 in cSCC tumors in vivo. The staining intensity of SerpinA1, EphB2 and AIM2 was significantly stronger in cSCC as compared with carcinoma in situ (cSCCIS) and actinic keratosis (AK). Tumor cell-associated SerpinA1 and EphB2 was noted in chemically induced mouse skin SCC, and the staining intensity was stronger in mouse cSCCs than in untreated skin. AIM2 staining intensity was significantly more abundant in cSCC of organ transplant recipients (OTR) than in sporadic cSCC in vivo. EphB2 knockdown resulted in inhibition of migration in cSCC cells. In addition, knockdown of EphB2 and AIM2 was found to inhibit the proliferation and invasion of cSCC cells and to delay the growth and vascularization of cSCC xenografts in vivo. Altogether, these findings identify SerpinA1 as a novel biomarker for cSCC. In addition, characterization of the roles of EphB2 and AIM2 in the progression of cSCC was implicated them as possible therapeutic targets for the treatment of cSCC particularly in unresectable and metastatic tumors.

Impacto de dos técnicas quirúrgicas sobre la recaída local de carcinoma de mama en pacientes de una clínica de Bogotá D.C.

Introducción: El carcinoma de mama es el tumor maligno más frecuente entre las mujeres y representa una significativa mortalidad en los países en vías de desarrollo. Según datos del Instituto Nacional de Cancerología en el 2010 se reportaron 672 nuevos casos de cáncer de mama, lo que representó el 18% de todos los tumores malignos en mujeres. Durante las últimas 3 décadas las técnicas quirúrgicas para el tratamiento del cáncer de mama han presentado un cambio significativo y proponen disminución de procedimientos agresivos y radicales, intervenciones como: mastectomía radical modificada, cirugía conservadora y la disección de ganglio centinela son ejemplos claros de esta evolución asociado al incremento de la reconstrucción mamaria inmediata. Metodología: Estudio observacional tipo cohorte retrospectivo en el cual se revisó una base de datos de pacientes con cáncer de mama de las cuales 632 fueron sometidas a mastectomía radical con preservación de piel y complejo areola-pezón y mastectomía radical con preservación de piel sin preservación del complejo areola-pezón, los dos procedimientos asociados a reconstrucción mamaria inmediata y se comparó la frecuencia de recaída local entre los dos grupos. Resultados: De las 632 pacientes estudiadas al 30.5% se les realizo preservación del complejo areola pezón. Las mujeres a quienes se les realizó preservación del complejo areola pezón presentaron menor sobrevida a la recaída local a 10 años (80.51%) comparado con las mujeres a quienes no se les preservó el complejo areola pezón (87.40%), sin embargo no se encontró diferencia estadísticamente significativa para determinar que las probabilidades de sobrevida sean diferentes. Discusión: No se evidenció diferencia estadísticamente significativa entre los 2 procedimientos quirúrgicos (con y sin preservación del complejo areola pezón) en relación a la recaída local, estudios retrospectivos no han evidenciado una mayor tasa de recaídas locales en pacientes a quienes se les preserva el complejo areola-pezón, sin embargo hacen falta estudios prospectivos y aleatorizados que puedan otorgar un mayor sustento científico que garantice la seguridad de la preservación del complejo areola-pezón.

Impacto de dos técnicas quirúrgicas sobre la recaída local de carcinoma de mama en pacientes de una clínica de Bogotá D.C.

Introducción: El carcinoma de mama es el tumor maligno más frecuente entre las mujeres y representa una significativa mortalidad en los países en vías de desarrollo. Según datos del Instituto Nacional de Cancerología en el 2010 se reportaron 672 nuevos casos de cáncer de mama, lo que representó el 18% de todos los tumores malignos en mujeres. Durante las últimas 3 décadas las técnicas quirúrgicas para el tratamiento del cáncer de mama han presentado un cambio significativo y proponen disminución de procedimientos agresivos y radicales, intervenciones como: mastectomía radical modificada, cirugía conservadora y la disección de ganglio centinela son ejemplos claros de esta evolución asociado al incremento de la reconstrucción mamaria inmediata. Metodología: Estudio observacional tipo cohorte retrospectivo en el cual se revisó una base de datos de pacientes con cáncer de mama de las cuales 632 fueron sometidas a mastectomía radical con preservación de piel y complejo areola- pezón y mastectomía radical con preservación de piel sin preservación del complejo areola-pezón, los dos procedimientos asociados a reconstrucción mamaria inmediata y se comparó la frecuencia de recaída local entre los dos grupos. Resultados: De las 632 pacientes estudiadas al 30.5% se les realizo preservación del complejo areola pezón. Las mujeres a quienes se les realizó preservación del complejo areola pezón presentaron menor sobrevida a la recaída local a 10 años (80.51%) comparado con las mujeres a quienes no se les preservó el complejo areola pezón (87.40%), sin embargo no se encontró diferencia estadísticamente significativa para determinar que las probabilidades de sobrevida sean diferentes. Discusión: No se evidenció diferencia estadísticamente significativa entre los 2 procedimientos quirúrgicos (con y sin preservación del complejo areola pezón) en relación a la recaída local, estudios retrospectivos no han evidenciado una mayor tasa de recaídas locales en pacientes a quienes se les preserva el complejo areola-pezón, sin embargo hacen falta estudios prospectivos y aleatorizados que puedan otorgar un mayor sustento científico que garantice la seguridad de la preservación del complejo areola-pezón.

Efeitos agudos do tratamento de radioterapia em doentes com carcinoma de cabeça e pescoço: IMRT vs RapidArc

A Radioterapia é parte integrante, standart, da abordagem multidisciplinar do tratamento de Carcinomas de Cabeça e Pescoço (CPP). A perceção e descrição dos efeitos provocados pelo tratamento ao nível dos tecidos normais é importante para avaliação clínica do doente, já que com o aparecimento de efeitos agudos severos/graves ao tratamento, este é interrompido, o que afetando diretamente a sobrevida do doente. Este estudo incidiu na avaliação de 6 semanas de tratamento de 46 doentes, contemplando a avaliação dos efeitos agudos do tratamento em cinco áreas anatómicas distintas: Pele, Mucosa, Glândulas Salivares, Faringe/Esófago e Laringe. Fundamentada nos critérios de classificação do Acute Radiation Morbidity Scoring Criteria da Radiation Therapy Oncology Group (RTOG). Após a avaliação e análise dos dados, verificou-se que os efeitos agudos obtidos com a técnica de RapidArcTM surgiram mais precocemente, quando comparados com técnica de IMRT. Por outro lado, com a técnica de IMRT registaram-se efeitos mais exacerbados, de alto Grau.

Long-term follow-up of topical 5-aminolaevulinic acid photodynamic therapy diode laser single session for non-melanoma skin cancer

Photodynamic therapy (PDT) is based on the association of a light source and tight sensitive agents in order to cause the selective death of tumor cells. To evaluate topical 5-aminolaevulinic acid (5-ALA) and diode laser photodynamic single session therapy single session for non-melanoma skin cancer (NMSC), a long-term follow-up was performed. Nineteen Bowen`s disease (BD) and 15 basal cell. carcinoma (BCC) lesions were submitted to 6-h topical and occlusive 20% 5-ALA plus DMSO and EDTA, and later were exposed to 630 nm diode laser, 100 or 300 J cm(-2) dose. At 3 months tumor-free rate was 91.2% (31/34) whereas at 60 months, 57.7% (15/26), slightly higher in BCC (63.6%; 7/11). The relation between the reduction of the clinical response and the increase of tumor dimension observed at 18 months was lost at 60 months. The sBCC recurrence was earlier compared to the nBCC one. ALA-PDT offered important advantages: it is minimally invasive, an option for patients under risk of surgical complications; clinical feasibility; treatment of multiple lesions in only one session or lesions in poor heating sites and superior esthetical results. However, the recurrence rate increase after ALA-PDT diode laser single session can be observed at tong-term follow-up, and the repetitive sessions, an additional. advantage of the method, is strongly recommended. The clinical response and recurrence time seem to be related to the laser light dose and NMSC types/sub-types, thickness and dimension, which must be considered for the choice of the ALA-PDT. (C) 2009 Elsevier B.V. All rights reserved.

Expressão da E-caderina em carcinoma de células escamosas e no tumor de células basais de cães

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Prevalência de lesões cutâneas actínicas em pacientes com carcinoma basocelular do segmento cefálico: um estudo caso-controle

OBJETIVO: Avaliar a prevalência de lesões cutâneas actínicas em portadores de carcinoma basocelular do segmento cefálico. MÉTODOS: Foi conduzido estudo tipo caso-controle. Os casos, constituídos por pacientes com carcinoma basocelular sólido, primário, menor que dois centímetros, no segmento cefálico; e controles, por pacientes com outras dermatoses. Foram analisadas variáveis constitucionais, comportamentais e lesões actínicas. RESULTADOS: Avaliaram-se 120 casos e 360 controles. Mílio facial (OR = 2,3), leucodermia puntacta de membros superiores (OR = 2,9) e cutis romboidalis nuchae (OR = 1,8) associaram-se à neoplasia independentemente das demais variáveis, sugerindo um fenótipo de risco. Houve ainda associação com fenótipos claros, genética familiar e exposição solar cumulativa. Queimadura solar, tabagismo e alcoolismo não foram identificados como fatores de risco. O uso de fotoprotetores não evidenciou proteção; porém, o grupo controle era composto por pacientes dermatológicos, aos quais são indicados fotoprotetores regularmente. CONCLUSÃO: Lesões actínicas foram mais prevalentes em portadores de carcinoma basocelular sólido do segmento cefálico que em controles, especialmente mílio, cutis romboidalis nuchae e leucodermia puntacta, independentemente dos demais fatores de risco conhecidos.

Frequência de ocorrência de carcinoma basocelular palpebral na região Centro-Oeste paulista e características dos portadores

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Perineural Invasion in Aggressive Skin Carcinomas of the Head and Neck

Introduction: Perineural invasion is a well-recognized form of cancer dissemination. However, it has been reported only in few papers concerning cutaneous carcinomas ( basal cell, BCC, and squamous cell, SCC). Moreover, the incidence is considered to be very low. Niazi and Lambert [Br J Plast Surg 1993; 46: 156-157] reported only 0.18% of perineural invasion among 3,355 BCCs. It is associated with high-risk subtypes, as morphea-like, as well as with an increased risk of local recurrence. No paper was found in the literature looking for perineural invasion in very aggressive skin cancers with skull base extension, with immunohistochemical analysis. Methods: This is a retrospective review, including 35 very advanced skin carcinomas with skull base invasion (24 BCCs and 11 SCCs, operated on at a single institution from 1982 to 2000). Representative slides were immunohistochemically evaluated with antiprotein S-100, in order to enhance nerve fibers and to detect perineural invasion. The results were compared to 34 controls with tumors with a good outcome, treated in the same time frame at the same Institution. Results: Twelve (50.0%) of the BCCs with skull base invasion had proven perineural invasion, as opposed to only 1 (4.6%) of the controls, and this difference was statistically significant (p < 0.001). Regarding SCCs, 7 aggressive tumors (63.6%) showed perineural invasion compared to only 1 (10.0%) of the controls, but this difference did not reach significance (p=0.08), due to the small number of cases. Conclusions: In this series, it was demonstrated that immunohistochemically detected perineural invasion was very prevalent in advanced skin carcinomas. In addition, it was statistically associated with extremely aggressive BCCs with skull base invasion. Copyright (c) 2008 S. Karger AG, Basel

Expression of apoptotic and cell proliferation regulatory proteins in keratoacanthomas and squamous cell carcinomas of the skin

The aim of this study was to investigate the expression of p53, caspase-3, bcl-2, MIB-1, and PCNA to validate more objective methods to differentiate squamous cell carcinoma and keratoacanthoma, as well as to understand their pathogenesis with accuracy. A total of 52 cases of histopathologically diagnosed keratoacanthoma in the proliferative stage and 56 cases of well-differentiated squamous cell carcinoma were selected in this study. The expression was evaluated by means of immunohistochemistry. Bcl-2 immunoreactivity was weak or absent in the majority of cases, either in squamous cell carcinoma or in keratoacanthoma. PCNA-positive cells did not show differences between two lesions evaluated. on the other hand, MIB-1 was statistically significant (p<0.05) between squamous cell carcinomas and keratoacanthomas. Moreover, p53 and caspase-3 were overexpressed in squamous cell carcinomas. Together, these results suggest that the biological behavior of the well-differentiated squanous cell carcinomas of the skin may be associated with cellular proliferation and/or deregulation of cell death, indicated by increased expression of the MIB-1 and apoptotic proteins p53 and caspase-3, respectively. (C) 2007 Elsevier GrnbH. All rights reserved.