Abstract
Cancer cells are exposed to a wide range of stress sources, such as nutrient deprivation and hypoxia, as well as cytotoxic chemotherapy and radiotherapy. Certain forms of stress can also promote survival activating the metabolic autophagy pathway in cancer cells. Autophagy is dramatically increased in cancer cells. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. Its role in tumorigenesis is more controversial and both the presence and the absence of autophagy have been implicated. Autophagy is known to be associated with the poor outcome of patients with various types of cancers, and its effectiveness as a prognostic marker in colorectal cancer was demonstrated by several studies. The inhibition of autophagy may be a potential therapeutic target in colorectal cancer. In vitro experiments have shown that the inhibition of autophagy increases 5-FU-induced apoptosis. There are two trials currently investigating the addition of chloroquine to 5-FU-based chemotherapy and bevacizumab. In the present study, we evaluated the expression of LC3B-II in samples of human colorectal microadenomas (i.e., dysplastic aberrant crypt foci) and carcinomas compared to normal mucosa. Furthermore, the expression pattern of LC3B-II was assessed in carcinomas classified as DNA microsatellite stable (MSS) and unstable (MSI). Thus, immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments were performed. The results clearly showed a significant increase in expression of the autophagic key factor in microadenomas and carcinomas with respect to normal mucosa. In MSS carcinomas, the level of LC3B-II expression was higher than that in the MSI carcinomas.
Highlights
It is an accepted concept of the cancer paradigm that tumorigenesis results from an imbalance between cell proliferation and cell death
We evaluated the expression of LC3B-II in samples of human colorectal microadenomas and carcinomas compared to normal mucosa
In order to evaluate the expression pattern of LC3B-II protein in the samples of normal colorectal mucosa (NM), microadenoma (MA) and colorectal cancer (CRC), immunofluorescence experiments coupled with confocal analysis were performed
Summary
It is an accepted concept of the cancer paradigm that tumorigenesis results from an imbalance between cell proliferation and cell death. It is becoming clearer that in response to cellular stress, cells may utilize multiple mechanisms that determine cell death or survival. Cancer cells utilize several mechanisms to withstand the cell death signals that are generated upon exposure to stress. Cancer cells undergoing certain forms of stress, such as starvation or hypoxia, can promote survival by modulating their intracellular metabolism [1]; for instance activation of the metabolic autophagy pathway. At least three distinct autophagic pathways are known: macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy is the most commonly studied form of autophagy in mammalian cells and is characterized by the sequestration of proteins and organelles, such as mitochondria, within an autophagosome [2]. An increase in LC3 was shown to be directly correlated with the number of autophagosomes and LC3B-II is considered to be the most specific marker of the autophagic process [4]
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