Abstract 3786: LC3B-positive autophagosomes are a common feature of solid tumors and associated with proliferation, metastasis and poor outcome

Abstract

Abstract Interest in autophagy and cancer has surged in recent years. Autophagy provides a source of nutrients in times of metabolic stress. A paradox for autophagy in cancer is that while autophagy is a conserved pro-survival mechanism, it can also act in tumor suppression as is the case with the autophagy-associated beclin-1 protein. However, there is growing evidence supporting a pro-survival role for autophagy in tumor progression, for example in gastrointestinal tumors and invasive melanomas wherein autophagosomes are abundant. Here we expanded previous studies on autophagosomes in malignancies to include nearly 2000 pathology specimens from 20 different cancers, analyzing for associations of autophagosomes with tumor progression. Methods. Individual pathology specimens and tumor tissue microarrays (TMAs) were stained for the autophagosome marker LC3B and the proliferation marker Ki-67 through standard IHC procedures. Automated quantitative analyses (AQUA) used fluorescence-tagged antibodies. Results: In multitumor TMAs, about 85% of all tumors showed positive staining of LC3B in a granular pattern. In melanoma TMAs, LC3B was elevated in lymph node metastases. In breast carcinoma TMAs LC3B was elevated in node-positive compared to node-negative primaries and associated with increased nuclear grade, and worse patient outcome. LC3B and Ki-67 expression correlated in both melanoma and breast carcinoma (p < 0.0001), indicating a strong association between autophagy and proliferation. Supporting this, mitotic figures were largely detected in LC3B-positive tumor cells. Conclusions. While it is clear that autophagy can play a tumor suppressor role in some settings, we posit that these results are most consistent with a pro-survival role for autophagy, at least in advanced malignancies. In cancer, autophagy is thought to be part of the pro-survival integrated stress response known as aerobic glycolysis or the Warburg effect whereby cells utilize glycolysis rather than aerobic respiration for ATP production. Since some 90% of malignancies constituitively express the Warburg effect and, as shown herein, a similar number express LC3B-positive autophagosomes, the results are most consistent with autophagy being an integral, active part of this response. That autophagosomes are expressed in proliferating tumor cells further supports this proposal. In any case, the widespread occurrence of autophagosomes in cancer shown herein, and by others, underscores the importance of autophagy as a target in the design of new anti-cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3786. doi:10.1158/1538-7445.AM2011-3786