Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation

Abstract

Autophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade. In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas. Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles. In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.

Immunohistochemical Expression of Autophagy-Related Proteins in Advanced Tubular Gastric Adenocarcinomas and Its Implications

“…From the archives of the Department of Human Pathology of Adult and Evolutive Age (University of Messina, Messina, Italy), a cohort of 32 cases of surgically resected gastric tubular type carcinomas were selected; twenty-five of them had been previously analyzed by EM and the morphological results have been already reported elsewhere [7]. Successively, seven additional cases were routinely processed for both light and electron microscopic observations.…”

“…This process removes damaged organelles and cytoplasmic proteins and incapsulates them in a double-membrane vesicle called autophagosome [2,3,4,5]. Once fused with lysosome, this vesicle realizes a single membrane autolysosome [4,6,7]. Many researchers are still investigating the role of autophagy in cancer and in multidrug resistance [5,6,7,8,9].…”

“…Once fused with lysosome, this vesicle realizes a single membrane autolysosome [4,6,7]. Many researchers are still investigating the role of autophagy in cancer and in multidrug resistance [5,6,7,8,9]. Indeed, autophagy has been considered a process that frequently supports progression in experimental and human tumors [2,7,8].…”

“…Since the most traditional morphological approach to assess autophagy is electron microscopy (EM) [3,8,10], we have already performed an ultrastructural investigation to assess autophagy in a cohort of advanced gastric adenocarcinomas [7]. In particular, it has been demonstrated that autophagic vacuoles (AV) represent a frequent finding in high-grade tubular carcinomas compared with low-grade ones [7]. Consequently, autophagy has been strictly related to cellular differentiation as well as tumor progression [7].…”

“…In particular, it has been demonstrated that autophagic vacuoles (AV) represent a frequent finding in high-grade tubular carcinomas compared with low-grade ones [7]. Consequently, autophagy has been strictly related to cellular differentiation as well as tumor progression [7].…”