HDAC Inhibitors as Epigenetic Regulators

Typically, these therapeutic agents inhibit molecular targets that regulate one or more cancer hallmark capabilities. initiation, subsequent to cellular transformation, tumors undergo dramatic evolution[1]. During this multistep process, studies have demonstrated that tumors abandon most of the key features associated with normal cells and acquire capabilities that serve the ultimate goal of sustaining tumor cell survival and proliferation[1]. Indeed, the functional role of each of the hallmarks of cancer including proliferative signaling, evading growth suppressors, resisting death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis either directly or indirectly promotes tumor cell survival and/or proliferation[1]. While these hallmarks are intrinsic to tumor cells, growing evidence suggests that it is the totality of the tumor microenvironment that determines the outcome of carcinogenesis[1-3]. The immune system is postulated to recognize tumors and to protect the host SOS1 from tumor development in a framework described as cancer immunosurveillance[4-6]. The immunosurveillance hypothesis envisaged that this function of effector leukocytes in defense against cancer would be necessary to maintain tissue homeostasis similar to its protective role against pathogenic microbes. Studies in mice have demonstrated that deficiency in recombination-activating gene (Rag)-1or-2required for the development of adaptive immunity results in increased frequency, shortened tumor latency, faster tumor growth kinetics of chemical-induced sarcomas and increased development of a broader spectrum of spontaneous tumors compared to age-matched wild type littermates[6-8]. Tumors that develop under immunodeficientRag-2knockout conditions are rejected when transplanted into wild type recipients but develop in hosts depleted of CD4+or CD8+T cells[7,9]. Moreover, tumors derived from wild type mice are not rejected when transferred into either wild type mice orRag-2-deficient hosts[7,9]. These findings support the immunosurveillance hypothesis and further demonstrate that T cells not only mediate tumor elimination but can also shape the immunogenicity of tumors. Recently, some effector mechanisms that mediate lymphocyte-dependent tumor rejection have been defined. Modification of tumor cells to secrete interferon (IFN)- resulted in the induction of persistent specific T cell immunity and a CD8+T cell-dependent tumor rejection whereas treatment of wild type mice with antibodies to neutralize endogenous IFN- led to failed rejection of carcinogen-induced tumors[10-12]. In addition to IFN-, the cytotoxic granule pathway has been shown to be essential for Benzocaine immunosurveillance. Deficiency in perforin, a crucial pore-forming protein required for the killer function of CTLs and natural killer cells results in development of fibrosarcomas with reduced latency and greater incidence and the mice further show greater susceptibility to the development of B cell lymphomas in comparison to control wild type mice[13-16]. These findings collectively underscore type 1-lymphocyte responses in the immunosurveillance of spontaneous and MCA-induced tumors. However, for the vast majority of tumor types, immune-mediated tumor rejection is not observed. In a transgenic model of sporadic cancer, the well-characterized SV40 Tag oncogene is stochastically activated leading to tumor development in diverse unpredictable tissues[17]. In this model, CD8+T cells recognize the Tag tumor-associated antigen but fail to kill target cells when testedin vivo[17]. In the TRAMP (transgenic adenocarcinoma of mouse prostate) model of prostate cancer, our recent findings, together with previous observations, demonstrated that HRC CD8+T cells specific for the TRAMP self-antigen histone H4 show functional defects [18,19]. CD8+T cells specific to tumor antigens have also been described in a subset of cancer patients but similar to the animal models, these T cells show limited effector activity[20,21]. These findings collectively suggest that T cells are able to recognize their cognate Benzocaine tumor antigens but the tumors avoid destruction by inducing T cell tolerance. How tumors initially prime T cell recognition and subsequently escape T cell-mediated eradication remains poorly understood. Understanding the mechanistic underpinnings of T cell tolerance in tumors is Benzocaine fundamental to the development of more effective anticancer therapies. It is conceivable that the six hallmarks of cancer that functionally converge on tumor cell survival and chronic proliferation can each influence antitumor immune response. Indeed, the acquisition of.