Targeting Autophagy in Cancer Therapy

Macroautophagy is a physiological cellular process that sequesters senescent or damaged organelles and proteins in autophagosomes for recycling of their products. Autophagy is also involved in the removal of cells that have undergone classical type 1 apoptosis. Hence, autophagy can be generally considered as a protector of cells against various stressors and a cellular response to routine wear-and-tear. On the other hand, autophagy may also lead to a form of non-apoptotic cell death, which is called type 2 programmed cell death. Thus, autophagy can either protect cells or promote cell death, depending on the cellular and environmental context. So far, contradictory data are available regarding the activity of autophagy and its regulation in cancer cells. In nonmalignant healthy tissues, autophagy seems to suppress the transition of normal to cancer cells. In addition, an exaggerated autophagy rate might drive neoplastic cells to death through several mechanisms, many of which are still not elucidated. Nevertheless, experimental evidence pointed at autophagy as a cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors cancer cell resistance to treatment. In the end, the role of autophagy in cancer is complex and it seems to depend on histology, stage, and multiple genetic variations and epigenetic changes. The tumor surrounding microenvironment exhibits a very complex set of interactions with autophagy at cancer tissues and represents another factor that is able to regulate tumor cell-kinetics and growth, as well as the response to therapies. In summary, while there is certain evidence that autophagy may act as a barrier to tumor initiation in some specific tissues, there is mounting evidence that autophagy has a significant pro-tumorigenic role in established cancers. Cancer therapies, including chemotherapy, radiotherapy and immunotherapy, are also associated with relevant changes into the autophagy intensity and flow. Some antineoplastic agents increase the autophagy rate; some other are associated with a reduction of the autophagy rate. Autophagy may modulate anticancer immunity by affecting several cellular and humoral mechanisms involved at these critical processes. Immunotherapeutic agents recently introduced in oncology clearly induce relevant modifications on autophagy flow in several tumor types. In addition, it has been demonstrated that certain non-antineoplastic drugs may exert some autophagy inducing effect on cancer cells. On the other hand, other agents block autophagy flow synergizing with the effect of some antineoplastic agents. Autophagy modulation is at this moment, a clear target for further development of cancer therapy. A description of the mechanisms that regulate autophagy in cancer cells and their surrounding micro-environment and the potential consequences of the pharmacologically induced modifications of these processes, constitute the main objective of this chapter.

Keywords: Apoptosis, Autophagy, Autophagosome, Molecular Mechanisms, Molecular Biomarkers, Oncology, Pancreatic Cancer.