Identificação de potenciais biomarcadores de caquexia no secretoma de carcinomas de pulmão de células não pequenas
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Data
2019-02-26
Autores
Cury, Sarah Santiloni
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A caquexia é uma síndrome metabólica complexa que frequentemente acomete pacientes portadores de neoplasia maligna em estádio clínico avançado. Caracteriza-se pela perda de massa muscular (com ou sem perda de tecido adiposo), a qual não pode ser completamente revertida por suporte nutricional. As vias moleculares responsáveis pela caquexia não estão completamente esclarecidas, entretanto, os avanços em estudos genômicos, transcriptômicos e proteômicos no câncer tem auxiliado na compreensão da importante relação entre o secretoma tumoral com alterações em órgãos e tecidos adjacentes ou distantes do tumor. Evidências têm demonstrado que componentes do secretoma do ambiente tumoral, incluindo citocinas pró-inflamatórias, possuem um papel fundamental no desenvolvimento de alterações metabólicas que resultam em sarcopenia (perda de função e massa muscular) em pacientes caquéticos. A perda de massa muscular é considerada um importante fator prognóstico de caquexia para pacientes com carcinomas de pulmão de células não pequenas (CPCNP) e, portanto, a avaliação de área muscular utilizando-se de tomografias computadorizadas (CTs) tem sido utilizada com grande eficácia para determinar a sobrevida e a presença de caquexia e sarcopenia nesses pacientes. Portanto, a hipótese desse trabalho é que a integração de dados clínicos e prognósticos, área dos músculos peitorais obtidas por CTs e perfil transcricional tumoral permitirá identificar potenciais biomarcadores de caquexia no secretoma de carcinomas de pulmão de células não pequenas. Para isso, 89 CTs de pacientes com CPCNP, disponíveis na plataforma TCIA (The Cancer Imaging Archive), foram analisadas para determinação da área dos músculos peitorais, a qual foi utilizada para seleção de pacientes com baixa ou alta muscularidade. A análise de expressão diferencial de genes do tumor desses mesmos pacientes foi realizada para selecionar transcritos com expressão aumentada no tumor de pacientes com baixa muscularidade. Destes, selecionamos os genes relacionados ao secretoma do tumor, a partir de análises in silico para predição de proteínas secretadas. Além disso, essas moléculas foram avaliadas quanto à sua classificação funcional e relação com dados clínicos dos pacientes. Nossos dados demonstram a relevância da citocina pró-inflamatória, Inteleucina-8, como potencial biomarcador de caquexia associado ao pior prognóstico de CPCNP. Esses dados são úteis para detecção precoce da caquexia e podem ter impacto na clínica de pacientes com CPCNP.
Cachexia is a metabolic syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of adipose tissue) that cannot be fully reversed by conventional nutritional support, most found in patients with advanced cancer. The molecular pathways of cancer cachexia are not completely known. The advances in genomic, transcriptomic and proteomic studies in cancer have helped in understanding the relationship of the tumor's secretome with changes in organs and tissues adjacent to or distant from the tumor. Evidences show that components of the tumor secretome, including pro-inflammatory cytokines, play a key role in metabolic alterations that result in sarcopenia (loss of muscle mass and function) of cachectic patients. Loss of skeletal muscle mass is important prognostic factor for cachexia in patients with non-small cell lung cancer (NSCLC), thus the evaluation of muscular area using computed tomography (CT) has been effective in determine survival and the presence of cachexia and sarcopenia in these patients. Therefore, our hypothesis is that the integration of clinical and prognostic data, pectoralis muscle area obtained by CTs, and tumor transcriptional profile will allow the identification of potential biomarkers of cachexia in the secretome of non-small cell lung carcinomas. To do this, 89 CTs from patients with NSCLC, available on the TCIA (The Cancer Imaging Archive) platform were used to measure the pectoralis muscle area, and to select patients with low or high muscularity. Differential gene expression analysis of tumor from these same patients was performed to select transcripts with increased expression in the tumor of low muscularity patients. Transcripts related to the tumor's secretome were selected through in silico prediction analyzes. In addition, these molecules were evaluated for their functional classification and relationship to the clinical data of each patient. Our results demonstrated the relevance of Interleukin-8 as potential biomarkers of cachexia associated with poor prognosis of patients with NSCLC. These data are useful for early detection of cachexia, which may have clinical impact in the management of patients with NSCLC.
Cachexia is a metabolic syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of adipose tissue) that cannot be fully reversed by conventional nutritional support, most found in patients with advanced cancer. The molecular pathways of cancer cachexia are not completely known. The advances in genomic, transcriptomic and proteomic studies in cancer have helped in understanding the relationship of the tumor's secretome with changes in organs and tissues adjacent to or distant from the tumor. Evidences show that components of the tumor secretome, including pro-inflammatory cytokines, play a key role in metabolic alterations that result in sarcopenia (loss of muscle mass and function) of cachectic patients. Loss of skeletal muscle mass is important prognostic factor for cachexia in patients with non-small cell lung cancer (NSCLC), thus the evaluation of muscular area using computed tomography (CT) has been effective in determine survival and the presence of cachexia and sarcopenia in these patients. Therefore, our hypothesis is that the integration of clinical and prognostic data, pectoralis muscle area obtained by CTs, and tumor transcriptional profile will allow the identification of potential biomarkers of cachexia in the secretome of non-small cell lung carcinomas. To do this, 89 CTs from patients with NSCLC, available on the TCIA (The Cancer Imaging Archive) platform were used to measure the pectoralis muscle area, and to select patients with low or high muscularity. Differential gene expression analysis of tumor from these same patients was performed to select transcripts with increased expression in the tumor of low muscularity patients. Transcripts related to the tumor's secretome were selected through in silico prediction analyzes. In addition, these molecules were evaluated for their functional classification and relationship to the clinical data of each patient. Our results demonstrated the relevance of Interleukin-8 as potential biomarkers of cachexia associated with poor prognosis of patients with NSCLC. These data are useful for early detection of cachexia, which may have clinical impact in the management of patients with NSCLC.
Descrição
Palavras-chave
Muscularidade, Secretoma, Interleucina-8, Tomografia computadorizada, C2C12, Muscularity, Secretome, Interleukin-8, Computed tomography