Identifying Critical Signaling Molecules for the Treatment of Cancer

Department of Medicine, Stanford University School of Medicine, CA 94305-5151, USA.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 02/2007; 172:5-24. DOI: 10.1007/978-3-540-31209-3_2
Source: PubMed


Tumorigenesis is a multistep process whereby an individual cell acquires a series of mutant gene products. These genetic changes
culminate in proliferation, growth, blocked differentiation, induction of angiogenesis, tissue invasion, and loss of genomic
stability. Given the genetic complexity of tumorigenesis, it is perhaps surprising that there are circumstances in which cancer
can be reversed through the repair or inactivation of individual mutant genes. However, recent experiments in transgenic mouse
models and clinical results with new pharmacological agents demonstrate that cancer can be treated through the targeted repair
and/or inactivation of mutant proteins. Hence, cancers appear to be dependent upon particular oncogenes to maintain their
neoplastic properties, thus exhibiting the phenomenon of “oncogene addiction.”

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    ABSTRACT: Cancer is caused by genetic changes that activate oncogenes or inactivate tumor suppressor genes. The repair or inactivation of mutant genes may be effective in the treatment of cancer. Indeed, drugs that target oncogenes can be effective in the treatment of cancer. However, it is still unclear why the inactivation of a single cancer-associated gene would ever result in the elimination of tumor cells. In experimental transgenic mouse models the consequences of oncogene inactivation depend upon the genetic and cellular context. In some cases, oncogene inactivation results in the elimination of all or almost all tumor cells through apoptosis by the phenomenon described as oncogene addiction. In other cases, oncogene inactivation predominantly results in the terminal differentiation or cellular senescence of tumor cells. In yet others, oncogene inactivation results in the apparent loss of the neoplastic properties of tumor cells, which now appear and behave like normal cells; however, upon oncogene reactivation at least some of these cells rapidly recover their neoplastic phenotype. Thus, oncogene inactivation can result in a state of tumor dormancy. Hence, understanding when and how oncogene inactivation induces apoptosis, differentiation, and senescence within a tumor will be important when developing effective strategies for the treatment of cancer.
    Full-text · Article · Jul 2008 · Apmis
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    ABSTRACT: Cancer is largely caused by genetic events that result in the mutation of oncogenes or tumor suppressor genes, leading to cell autonomous proliferation and growth. The repair of these mutant gene products may be expected to subvert this neoplastic behavior. Indeed, oncogene inactivation can result in the elimination of all or almost all tumor cells by various mechanisms through the phenomena described as oncogene addiction. Recently, we have shown that oncogene addiction occurs through at least two broad classes of mechanisms: tumor cell intrinsic mechanisms of cellular senescence and apoptosis; and tumor cell extrinsic host-dependent mechanisms that include the shut-down of angiogenesis. We have argued that the abatement of oncogenic activity within a cancer cell not only leads to the demise of a tumor from within but also through the instruction of the restoration of the microenvironment.
    No preview · Article · Jan 2009 · Lymphatic Research and Biology
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    ABSTRACT: Tumorigenesis is generally caused by genetic changes that activate oncogenes or inactivate tumor suppressor genes. The targeted inactivation of oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. One of the most common oncogenic events in human cancer is the activation of the MYC oncogene. The inactivation of MYC may be a general and effective therapy for human cancer. Indeed, it has been experimentally shown that the inactivation of MYC can result in dramatic and sustained tumor regression in lymphoma, leukemia, osteosarcoma, hepatocellular carcinoma, squamous carcinoma, and pancreatic carcinoma through a multitude of mechanisms, including proliferative arrest, terminal differentiation, cellular senescence, induction of apoptosis, and the shutdown of angiogenesis. Cell-autonomous and cell-dependent mechanisms have both been implicated, and recent results suggest a critical role for autocrine factors, including thrombospondin-1 and TGF-β. Hence, targeting the inactivation of MYC appears to elicit oncogene addiction and, thereby, tumor regression through both tumor cell-intrinsic and host-dependent mechanisms.
    Full-text · Article · Aug 2010 · Genes & cancer