RESUMO
INTRODUCTION: The effects of low-dose alcohol consumption on colorectal cancer development are not well understood. Epidemiological studies have reported that people who consume small amounts of alcohol have lower mortality rates than both nondrinkers and heavy drinkers. This phenomenon has been labeled the "J-curve effect" of alcohol. This study examined the effects of low-dose alcohol (0.5%, 1%, and 2%) on tumor growth in a transplant colon cancer model. METHODS: BALB/c and BALB/c nude mice were used to analyze T-cell immunity. Syngeneic CT26 murine colon cancer cells were implanted into the cecal wall, and the resulting T-cell immune effects were monitored. RESULTS: The growth of orthotopic tumors was markedly inhibited upon ingestion of low-dose (0.5%) alcohol compared with that in the control mice. In contrast, cells from the same line were injected into the cecal wall of nude mice, and tumor growth inhibition was not observed. Histopathological and RNA sequence analyses were performed to elucidate the mechanisms underlying tumor growth inhibition. An increase in tumor CD8+ T lymphocytes and changes in cytokine levels were observed. Microbiome analysis using 16S rRNA gene sequencing of cecal contents was performed and revealed Mucispirillum schaedleri and Clostridium cocleatum showed decreased and increased abundance, respectively, in the alcohol group. DISCUSSION/CONCLUSION: Ingesting a threshold amount of alcohol results in the infiltration of T lymphocytes, which may enhance immune responsiveness in mouse colorectal cancer models.
Assuntos
Neoplasias do Colo , Animais , Camundongos , Camundongos Nus , RNA Ribossômico 16S , Neoplasias do Colo/patologia , Linfócitos T CD8-Positivos , Citocinas , Etanol , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Linhagem Celular TumoralRESUMO
Macrophages are an essential component of antitumor activity; however, the role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM-CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM-CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM-CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan-, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.
Assuntos
Neoplasias Colorretais/patologia , Macrófagos Associados a Tumor/fisiologia , Idoso , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Contagem de Células , Diferenciação Celular , Neoplasias Colorretais/imunologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Imunofluorescência/métodos , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Fenótipo , Curva ROC , Receptores de Superfície Celular/análise , Microambiente Tumoral , Macrófagos Associados a Tumor/citologiaRESUMO
Fatty liver is the most common cause of liver disease, and its prevalence has been increasing globally. Colorectal cancer (CRC) accounts for approximately 10% of all cancers and metastasizes most commonly to the liver. Paget's 'Seed and Soil' theory of metastasis proposed that the secondary growth of cancer cells is dependent on the distal organ microenvironment. This implies that the risk of metastasis may change due to changes in the microenvironment of target organs. However, the association between steatosis, fatty change in the liver microenvironment, and liver metastasis has not been clarified. Here, we induced fatty liver conditions in BALB/c mice using a choline-deficient high-fat diet with 0.1% methionine (CDAHFD) and then injected the CT26 cells to produce experimental metastasis. The number of metastatic tumours was significantly increased in mice with severe fatty liver as compared to control mice. The average size of metastatic tumours was smaller in mice with moderate fatty liver than in control mice. The stromal components, including cancer-associated fibroblasts, tumour-associated macrophages and tumour-infiltrating lymphocytes, were also examined. Metastatic tumours in fatty liver showed invasive growth patterns without a fibrotic capsule. Compared to control groups, the polarization of macrophages and subtypes of tumour-infiltrating lymphocytes differed depending on the extent of fatty liver progression. These results indicated that fatty changes in the liver influenced liver metastasis of CRC. Although moderate fatty changes suppress the growth of metastatic tumours in the liver, a severe fatty microenvironment may promote invasion and metastasis through alteration of the tumour microenvironment (TME).