In some cases, the inactivation of the oncogene fails to cause significant tumour regression such as in a murine model of MYC-induced lung adenocarcinoma [14]. Thus, in many but not all cases, the inactivation of an oncogene that initiates tumorigenesis is sufficient to reverse tumorigenesis. The clinical relevance of oncogene addiction was ensconced more firmly after the development of several effective targeted

therapeutics [15,16]. The advent of potent agents such as imatinib for chronic myelogenous leukaemia and gastrointestinal stromal tumours [17], trastuzumab for the treatment of breast cancer [18] and PLX4032 for the treatment of melanoma [19], among other drugs [20], has galvanized interest in exploiting oncogene addiction SCH727965 datasheet for cancer therapy and understanding the underlying principles by which it works. The mechanism of oncogene addiction has been largely presumed to be cell autonomous and to occur by processes intrinsic and exclusively dependent upon biological programmes within a tumour cell. Several mechanisms have been proposed for oncogene addiction, including the notion of abnormal tumour cell genetic circuitry [21], reversibility of tumorigenesis [22], oncogenic shock [23] and synthetic lethality

[24]. However, the host microenvironment is well established to play a critical role in how oncogenes initiate tumorigenesis [25–28], suggesting strongly that host factors might similarly play an important role in oncogene addiction. The notion of an intimate relationship between tumour cells and host immune cells was first posited more than a century Racecadotril ago by Rudolf Virchow [29]. The immune system is integral to almost every aspect of tumorigenesis, BGB324 concentration including tumour initiation [30,31], prevention [32] and progression [33]. Tumours appear to undergo immune editing that is important to both their generation and therapeutic destruction [34,35]. Tumorigenesis is a consequence of interactions between incipient neoplastic cells and host stromal cells, including immune cells, endothelial cells and fibroblasts, as well as extracellular

matrix components and secreted factors [25]. The immune system plays a complex role in tumorigenesis [36], and immune effectors and their secreted factors have been implicated in the initiation of tumorigenesis [30,31], tumour growth, survival and metastastic dissemination as well as in immune surveillance and prevention of tumour growth [36]. Correspondingly, in mouse models and in human patients, various components of the immune system have been implicated in tumorigenesis. Immune effectors including macrophages, T and B cells have been shown to either have a role in promoting [37–39] or inhibiting [40–43] tumour growth, depending on the particular neoplastic context. Moreover, other immune cells such as natural killer (NK) cells [44] can inhibit metastasis, whereas CD4+ T cells [45] and macrophages [46] have been shown to promote metastasis.