Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti-LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease-free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer. (Cancer Sci 2008; 99: 1813-1819) C ancers are abnormal tissue masses whose growth exceeds and is uncoordinated with that of adjacent normal tissues, and which persist in the same excessive manner after cessation of the stimulus that evoked them.(1) All cancers ultimately depend on the host for their nutrition and blood supply, but as the preexisting vasculature is obviously insufficient to support the cancers' unlimited requirements for energy and nutrition as a result of their unregulated growth, angiogenesis has been considered pivotal to providing proliferating cancer cells with an adequate source of oxygen, energy, and nutrients. However, recent studies have revealed that even after new blood vessels have formed, both the oxygen and glucose supply is insufficient for the aggressively proliferating cancer cells in locally advanced cancers.(2-4) Tumor hypoxia has been used as a marker of poor prognosis; (5,6) however, how cancer cells become more malignant or survive with an extremely poor blood supply, as for example in pancreatic cancer, is poorly understood.(7) When cancer cells are exposed to hypoxia, anaerobic glycolysis increases and provides energy for cell survival, but as the glucose supply is also insufficient because of the poor blood supply, there must be an alternative metabolic pathway that provides energy when both oxygen and glucose are depleted. (8,9) We have reported that several cancer cell lines, including pancreatic cancer-and colorectal cancer-derived cell lines, are resistant to nutrient-deprived co...