Mitochondrial Function Differences between Tumor Tissue of Human Metastatic and Premetastatic CRC

Abstract

[eng] Metastasis is an important cause of death from colorectal cancer (CRC). Mitochondria, which are important organelles of cells, play a key role in the metastatic transformation of cancer cells. We aimed to evaluate the adaptations associated with mitochondrial function in tumor tissues from advanced stages of human CRC and whether they could ultimately be used as a therapeutic target in metastatic CRC. We have compared the mitochondrial functionality parameters in tumor tissue samples and the normal adjacent tissue of advanced CRC patients with no radio- or chemotherapy treatment before surgery. Notable differences in mitochondrial functionality were detected between the samples of adjacent tissue versus tumor tissue from metastatic CRC patients. These findings suggest a shift in the mitochondrial function profile occurring in tumor tissue once the metastatic stage has been reached. These changes contribute to promote and maintain the metastatic phenotype, with evidence of mitochondrial function impairment in tumor tissue in the metastatic stage samples. Most colorectal cancer (CRC) patients die as a consequence of metastasis. Mitochondrial dysfunction could enhance cancer development and metastatic progression. We aimed to evaluate the adaptations associated with mitochondrial function in tumor tissues from stages III and IV of human CRC and whether they could ultimately be used as a therapeutic target in metastatic colorectal cancer (mCRC). We analyzed the protein levels by Western blotting and the enzymatic activities of proteins involved in mitochondrial function, as well as the amount of mitochondrial DNA (mtDNA), by real-time PCR, analyzing samples of non-tumor adjacent tissue and tumor tissue from stages III and IV CRC patients without radio- or chemotherapy treatment prior to surgery. Our data indicate that the tumor tissue of pre-metastatic stage III CRC exhibited an oxidant metabolic profile very similar to the samples of non-tumor adjacent tissue of both stages. Notable differences in the protein expression levels of ATPase, IDH2, LDHA, and SIRT1, as well as mtDNA amount, were detected between the samples of non-tumor adjacent tissue and tumor tissue from metastatic CRC patients. These findings suggest a shift in the oxidative metabolic profile that takes place in the tumor tissue once the metastatic stage has been reached. Tumor tissue oxidative metabolism contributes to promote and maintain the metastatic phenotype, with evidence of mitochondrial function impairment in stage IV tumor tissue.