がんの科学と治療

Despite the remarkable progress made in delineating the pathogenesis of ovarian tumor during the last two decades, the 5 years survival of these patients is very low, with 80% of them succumbing to their resistant disease. Understanding the key determinants of this resistance is of paramount importance if the prognosis of this tumor has to be improved. Here are summarized the role of cancer stem cells and epithelial to mesenchymal transition (EMT) in determining tumor recurrence in ovarian cancer. Indeed, the existence, and more importantly the acquisition of stem-cell traits by tumor cells both during tumor progression and during treatment might explain the ability of these cells to give rise to tumor recurrence and to be resistant to treatment.

Malignant mesothelioma (MM) is a deadly cancer caused by asbestos exposure that is increasing worldwide. Early diagnosis for this cancer is very difficult and MM is mostly resistant to conventional therapies. A host of factors may be responsible for development of MM and imparting drug resistance to this cancer. Understanding these processes will be important in designing therapeutic approaches for MM. Some of the conventional as well as current approaches for MM therapy are discussed in this review.

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor produced by the endothelium. Here we examined the efficacy of local adenovirus-mediated VASH1 gene transfer for anti-angiogenic cancer treatment. When non-proliferative adenovirus vector encoding the human VASH1 gene (AdhVASH1) was injected locally into the peritoneal cavity and HM-1 ovarian cancer cells were inoculated into the peritoneal cavity thereafter, we observed a significant inhibition of tumor angiogenesis. However, to our surprise, when HM-1 cells were infected with AdhVASH1 (HM-1/hVASH1) and then inoculated in mice, we observed a paradoxical augmentation of tumor angiogenesis and tumor growth. To explore the mechanism of this augmented tumor angiogenesis, we investigated the expression of various angiogenesis regulators. The level of angiogenesis stimulators such as VEGF and FGF-2 was unchanged; however we noticed a marked down-regulation of one angiogenesis inhibitor, namely interferon- γ-inducible protein-10 (IP-10). Moreover, this down-regulation of IP-10 and augmented tumor angiogenesis were not seen when HM-1/hVASH1 cells were inoculated into severe combined immunodeficiency mice. Our present analysis reveals that there is a mutual interaction between 2 angiogenesis inhibitors; VASH1 and IP-10, and the immune reaction might be responsible for this interaction through hitherto unknown mechanism. It also discloses the importance of endogenous IP-10 in tumors, as down-regulation of IP-10 results in the paradoxical augmentation of tumor angiogenesis. Care must be taken when VASH1 gene is transiently transferred to cancer cells for the antiangiogenesis treatment.

Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Historically, chemotherapy or radiotherapy did not provide significant survival benefit in advanced pancreatic cancer. Thus, new therapeutic approaches are needed. As there is strong evidence that vaccine therapy against pancreatic cancer elicits antitumor immune responses, scientists have tried to stimulate the antitumor activities of the immune system to fight against pancreatic cancer, but has not reached to an expected result. Pancreatic cancer activates both antitumor immune responses and immunosuppressive mechanisms leading to tumor development and progression. This action is achieved through mobilization and activation of immune suppressive cells (CAFs), tolerogenic DCs, MDSCs, TAMs, Treg cells and cancer cells-derived soluble factors that promote the induction of tolerance through the generation of CD4+αchain of IL-2R (CD25)+forkhead box P3 (Foxp3) subset. In addition, pancreatic cancer cells modulate the immune system and avoid detection by effector immune by production of immune suppressive cytokines (e.g., TGF-β, IL-10, and IL-6), by expressing surface molecules that mediate immune suppression (e.g., vascular endothelial growth factors (VEGFs), Fas ligand (Fas-L), programmed death-1 ligand (PD-L1), indolamine-2, and 3-dioxygenase (IDO). Identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. Vaccine therapy relies on the administration of biological preparations that include an antigen that is specifically expressed by malignant cells, boosting the natural ability of the immune system to react against neoplastic cells. Potent vaccines stimulate antigen presentation by dendritic cells, hence driving the expansion of antigen-specific effector and memory T cells. Further, immune modulation and immunosuppressive environment by pancreatic cancer can be overcome by enhancing vaccine efficacy by combinatorial therapy. In this paper, we analyze recent preclinical and clinical efforts towards vaccine therapy for pancreatic cancer designed to target pancreatic cancer-associated antigens and to elicit an antitumor response in vivo.