Investigação da expressão de marcadores de células tronco neoplásicas (CTNs), de proliferação e de inflamação no câncer de mama e sua associação com as características clinicopatológicas da doença e com a obesidade
Izabel Cristina da Rocha Leão Crivelli Nunes da Silva
DISSERTAÇÃO
Português
T/UNICAMP Si38i
[Investigation of the expression of markers of cancer stem cells (CSC), proliferation and inflammation in breast cancer and its association with the clinical-pathological characteristics of the disease and with obesity]
Campinas, SP : [s.n.], 2022.
1 recurso online (102 p.) : il., digital, arquivo PDF.
Orientadores: Sílvia de Barros Mazon, Cassio Cardoso Filho
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Resumo: A obesidade é caracterizada pela inflamação crônica subclínica no tecido adiposo, que produz adipocitocinas pró-inflamatórias tais como o fator de necrose tumoral alfa (TNF-?), a Interleucina-6 (IL-6) e a proteína amilóide sérica A (SAA). A inflamação crônica tem sido associada aos processos...
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Resumo: A obesidade é caracterizada pela inflamação crônica subclínica no tecido adiposo, que produz adipocitocinas pró-inflamatórias tais como o fator de necrose tumoral alfa (TNF-?), a Interleucina-6 (IL-6) e a proteína amilóide sérica A (SAA). A inflamação crônica tem sido associada aos processos de gênese, progressão e metástase tumoral e contribui para o desenvolvimento de células tronco neoplásicas (CTNs), que possuem capacidade de autorrenovação e diferenciação em linhagens múltiplas. A presença de CTNs mamárias está associada a prognóstico desfavorável, resistência à quimio e à radioterapia. Este trabalho investigou a expressão tecidual de marcadores de CTNs (enzima aldeído desidrogenase 1 – ALDH1, glicoproteína de membrana CD44 e fator de transcrição ligador de octâmero 4 – Oct4), de proliferação (Ki-67) e de inflamação (TNF-?, IL-6 e SAA) no câncer de mama e sua relação com as características clinicopatológicas da doença, com a obesidade e com parâmetros associados a ela. A expressão dos marcadores teciduais foi investigada em dois conjuntos de microarranjos de tecidos (tissue microarray – TMA), construídos a partir das regiões tumoral (TU) e não tumoral (NT) de espécimes cirúrgicos de 90 pacientes, classificadas em grupo de não obesas (NO) e grupo com sobrepeso/obesidade (SP/O). As análises comparativas entre variáveis contínuas foram realizadas pelo teste de Mann-Whitney, as de associação entre variáveis categóricas pelo teste x2 ou exato de Fisher e as de correlações entre variáveis contínuas pelo teste de Spearman. Para análise de sobrevida livre de doença (SLD) e sobrevida global (SG) foi utilizado o método de Kaplan-Meier, com comparação entre curvas pelo teste log-rank. Para avaliação dos fatores associados à SLD e à SG foi utilizada a análise de regressão de Cox, simples e múltipla. O nível de significância adotado foi de 5% (p < 0,05). A análise do conjunto total de amostras demonstrou expressão diferencial entre os TMAs TU e NT para os marcadores ALDH1, Oct4, Ki-67 e SAA, resultado que permaneceu quando as análises foram direcionadas para as amostras dos grupos NO e SP/O. Não foram detectadas diferenças de expressão de qualquer marcador tecidual entre os TMAs dos grupos NO e SP/O, entretanto foram observadas relações da expressão de alguns marcadores com parâmetros relacionados à obesidade, tais como: ALDH1 no epitélio TU com SAA sérica; TNF-? TU com níveis de colesterol total e LDL-colesterol, IL-6 TU com SAA sérica e associação inversa entre Ki-67 TU e níveis de HDL-colesterol. As principais associações entre os marcadores teciduais com as características clinicopatológicas da doença foram: ALDH1 no epitélio TU com estadios mais avançados de Ecp, CD44 no epitélio TU com tumores de GN mais avançados e IL-6 TU com tumores de GH mais avançados. A análise de regressão de Cox múltipla demonstrou influência dos marcadores ALDH1 no estroma TU e IL-6 TU sobre SLD, ou seja: a ausência do marcador ALDH1 no estroma TU apresenta risco de recidiva 13,2 vezes maior e a expressão de IL-6 TU aumenta o risco de recidiva em 7,6 vezes a cada unidade (escore). Em relação à SG, a análise de regressão de Cox múltipla demonstrou que a expressão de IL-6 TU aumenta o risco de óbito em 4,3 vezes a cada unidade (escore). As influências da ALDH1 no estroma TU sobre a SLD e da IL-6 TU sobre as SLD e SG, observadas no presente trabalho, corroboram as observações experimentais reportadas na literatura e estimulam novas frentes de investigação voltadas para a área terapêutica
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Abstract: Obesity is characterized by chronic subclinical inflammation in adipose tissue, which
produces pro-inflammatory adipocytokines such as tumor necrosis factor alpha (TNF-a), Interleukin-6 (IL-6), and serum amyloid A protein (SAA). Chronic inflammation has been associated with the processes... Ver mais Abstract: Obesity is characterized by chronic subclinical inflammation in adipose tissue, which
produces pro-inflammatory adipocytokines such as tumor necrosis factor alpha (TNF-a), Interleukin-6 (IL-6), and serum amyloid A protein (SAA). Chronic inflammation has been associated with the processes of tumor genesis, progression, and metastasis and contributes to the development of cancer stem cells (CSCs), which have the capacity for self-renewal and differentiation into multiple lineages. The presence of breast CSCs is associated with unfavorable prognosis, resistance to chemo and radiotherapy. This work investigated the tissue expression of CSCs markers (aldehyde dehydrogenase enzyme 1 – ALDH1; membrane glycoprotein CD44, and octamer binding transcription factor 4 – Oct4), proliferation marker (Ki-67) and inflammation markers (TNF-a, IL-6 and SAA) in breast cancer and their relationship with the clinicopathological characteristics of the disease, with obesity and with parameters associated with it. The expression of tissue markers was investigated in two sets of tissue microarrays (TMA), constructed from the tumor (TU) and non-tumor (NT) regions of surgical specimens from 90 patients, classified into a non-obese group (NO) and overweight/obese group (SP/O). The Mann-Whitney test was used to compare continuous variables, the x2 or Fisher's exact test was used for the association between categorical variables and Spearman's test for correlations between continuous variables. For analysis of disease-free survival (DFS) and overall survival (OS), the Kaplan-Meier method was used, with the comparison between curves using the log-rank test. Cox regression analysis, simple and multiple, was used to evaluate the factors associated with DFS and GS. The significance level adopted was 5% (p < 0.05). Analysis of the total set of samples demonstrated differential expression for the markers ALDH1, Oct4, Ki-67 and SAA between TU and NT TMAs, a result that remained when the analyzes were directed to samples from the NO and SP/O groups. No differences in the expression of any tissue marker were detected between the TMAs of the NO and SP/O groups, however, relationships of the expression of some markers with obesity-related parameters were observed, such as: ALDH1 in the TU epithelium with serum SAA; TNF-a TU with total cholesterol and LDL-cholesterol levels; IL-6 TU with serum SAA, and inverse association between Ki-67 TU and HDL-cholesterol levels. The main associations between tissue markers and clinicopathological features of the disease were: ALDH1 in TU epithelium with more advanced stages of the disease, CD44 in TU epithelium and IL-6 TU with more advanced tumors. Multiple Cox regression analysis demonstrated the influence of ALDH1 in the TU stroma and IL-6 TU on DFS, i.e.: absence of the ALDH1 marker in the TU stroma presents 13.2-fold increased risk of recurrence and expression of IL-6 TU increases the risk of recurrence by 7.6-fold for each unit (score). Regarding OS, multiple Cox regression analysis demonstrated that IL-6 TU expression increases the risk of death by 4.3-fold for every unit (score). The influences of ALDH1 in the TU stroma on DFS and of IL-6 TU on DFS and SG, observed in the present study, corroborate the experimental observations reported in the literature and stimulate new research approaches focused on the therapeutic
area Ver menos
produces pro-inflammatory adipocytokines such as tumor necrosis factor alpha (TNF-a), Interleukin-6 (IL-6), and serum amyloid A protein (SAA). Chronic inflammation has been associated with the processes... Ver mais Abstract: Obesity is characterized by chronic subclinical inflammation in adipose tissue, which
produces pro-inflammatory adipocytokines such as tumor necrosis factor alpha (TNF-a), Interleukin-6 (IL-6), and serum amyloid A protein (SAA). Chronic inflammation has been associated with the processes of tumor genesis, progression, and metastasis and contributes to the development of cancer stem cells (CSCs), which have the capacity for self-renewal and differentiation into multiple lineages. The presence of breast CSCs is associated with unfavorable prognosis, resistance to chemo and radiotherapy. This work investigated the tissue expression of CSCs markers (aldehyde dehydrogenase enzyme 1 – ALDH1; membrane glycoprotein CD44, and octamer binding transcription factor 4 – Oct4), proliferation marker (Ki-67) and inflammation markers (TNF-a, IL-6 and SAA) in breast cancer and their relationship with the clinicopathological characteristics of the disease, with obesity and with parameters associated with it. The expression of tissue markers was investigated in two sets of tissue microarrays (TMA), constructed from the tumor (TU) and non-tumor (NT) regions of surgical specimens from 90 patients, classified into a non-obese group (NO) and overweight/obese group (SP/O). The Mann-Whitney test was used to compare continuous variables, the x2 or Fisher's exact test was used for the association between categorical variables and Spearman's test for correlations between continuous variables. For analysis of disease-free survival (DFS) and overall survival (OS), the Kaplan-Meier method was used, with the comparison between curves using the log-rank test. Cox regression analysis, simple and multiple, was used to evaluate the factors associated with DFS and GS. The significance level adopted was 5% (p < 0.05). Analysis of the total set of samples demonstrated differential expression for the markers ALDH1, Oct4, Ki-67 and SAA between TU and NT TMAs, a result that remained when the analyzes were directed to samples from the NO and SP/O groups. No differences in the expression of any tissue marker were detected between the TMAs of the NO and SP/O groups, however, relationships of the expression of some markers with obesity-related parameters were observed, such as: ALDH1 in the TU epithelium with serum SAA; TNF-a TU with total cholesterol and LDL-cholesterol levels; IL-6 TU with serum SAA, and inverse association between Ki-67 TU and HDL-cholesterol levels. The main associations between tissue markers and clinicopathological features of the disease were: ALDH1 in TU epithelium with more advanced stages of the disease, CD44 in TU epithelium and IL-6 TU with more advanced tumors. Multiple Cox regression analysis demonstrated the influence of ALDH1 in the TU stroma and IL-6 TU on DFS, i.e.: absence of the ALDH1 marker in the TU stroma presents 13.2-fold increased risk of recurrence and expression of IL-6 TU increases the risk of recurrence by 7.6-fold for each unit (score). Regarding OS, multiple Cox regression analysis demonstrated that IL-6 TU expression increases the risk of death by 4.3-fold for every unit (score). The influences of ALDH1 in the TU stroma on DFS and of IL-6 TU on DFS and SG, observed in the present study, corroborate the experimental observations reported in the literature and stimulate new research approaches focused on the therapeutic
area Ver menos
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Aberto
Barros-Mazon, Silvia de, 1956-
Orientador
Cardoso Filho, Cassio, 1974-
Coorientador
Santos, Magnun Nueldo Nunes dos, 1984-
Avaliador
Gonçalves, Rodrigo, 1982-
Avaliador
Investigação da expressão de marcadores de células tronco neoplásicas (CTNs), de proliferação e de inflamação no câncer de mama e sua associação com as características clinicopatológicas da doença e com a obesidade
Izabel Cristina da Rocha Leão Crivelli Nunes da Silva
Investigação da expressão de marcadores de células tronco neoplásicas (CTNs), de proliferação e de inflamação no câncer de mama e sua associação com as características clinicopatológicas da doença e com a obesidade
Izabel Cristina da Rocha Leão Crivelli Nunes da Silva