Pancreatic Cancer Is Not Noble

low [10, 11] , epithelial and stromal cells turn to autophagy [12–14] . Without a proper interaction with adjacent stroma, substrate provision to the tissues cannot be maintained. When this programmed survival pathway fails, epithelial cells die a necrotic death and release DAMPs. These include HMGB1 [1–9, 11–14] , as reported by Nace et al. [15] and Berthelot et al. [16] in this issue of the Journal of Innate Immunity . Stromal cells respond by providing substrate to the metabolically stressed epithelial cells. We hypothesize that DAMPs perpetuate this shift in bioenergetics, promoting further autophagy [12–14] . The receptors that play a role, including RAGE (receptor for advanced glycation end products) [2, 14] , as reported by Dessing et al. [17] in this issue, appear to be important for the response to low levels of HMGB1 but not to higher levels, where Toll-like receptor 2 and Toll-like receptor 4 (TLRs) play predominant roles. Other receptors include the NOD1/NALP-like receptors (NLRs) as put forward by Mason et al. [18] , the RIG-I receptors (RLRs) and the AIM2-like DNA receptors (ALRs). Other proteins apart from HMGB1 play a role as DAMPs. In addition to heat shock factors (reviewed in part by Gally et al. [19] in this issue) and the S100 molecules (also reviewed in this issue, by Srikrishna [20] ), extracellular proteins such as hyaluronan, heparin sulfate and fibronectin (Sofat et al. [21] , in this issue) also play a role in alerting the innate immune response. Much clearly remains to be done to resolve the important role of these molecules in disease. For the last century, immunity was based on specificity, first, serological responses, and then over the last three decades, T cell immunity. We now recognize that innate immunity represents the solid core of immunity on which adaptive responses have been draped. This has most recently been acknowledged with the 2011 Nobel Prize in Physiology or Medicine being awarded to Bruce Beutler, Jules Hoffman and Ralph Steinman. As many of our readers know, our friend Dr. Ralph Steinman was afflicted by pancreatic cancer, working tirelessly for almost 5 years with immune therapies to alter his disease trajectory. Sadly, he never knew of the prize awarded to him, dying a scant few days before it was announced. We dedicate this issue of the Journal of Innate Immunity to his memory.