Abstract
This week’s issues of Science and Science’s STKE are devoted to cancer research and to exploring how recent discoveries may impact our ability to diagnose and treat cancer. Science's STKE focuses on mechanisms by which growth factor–mediated stimulation of hypoxia-inducible factor signaling contributes to cancer progression and research that suggests a role as a tumor suppressor for a splicing variant of the c-H-ras oncogene.
The author of the earliest known description of human cancer, preserved on an ancient Egyptian papyrus, believed that cancer was incurable; Hippocrates, who gave the disease its name, held similar views. The advent in the mid-20th century of cancer chemotherapy involving drugs that interfere with DNA synthesis or cell division, or agents that damage DNA, led to dramatic cures of certain forms of cancer. The knowledge that even advanced cancers could be cured led to the hope—even the expectation—that a deeper understanding of the biological bases of cancer would swiftly lead to the conquest of this dread group of diseases. As Varmus notes in his Science Perspective, such changes have been achingly slow to materialize: The age-adjusted mortality for most forms of cancer has improved little over the past 50 years, and the tremendous advances in our understanding of the biology of cancer that have taken place since then have had little apparent impact on its therapy. However, advances over the past decade or so have given us hope that this situation is poised to change. This week’s issues of Science and Science’s STKE are devoted to exploring the current status of cancer research and how new insights into the molecular bases of cancer and the behavior of cancer cells may lead to pivotal changes in our abilities to diagnose and treat cancer (www.sciencemag.org/sciext/cancer/).
Varmus provides an overview of the field in a Science Perspective describing how our increased understanding of the mutations that drive cancer and of the physiology of cancer cells promises to lead to improvements in cancer diagnosis and therapy. Among the exciting areas highlighted is the notion of oncogene addiction—the idea that cancer cells become so dependent on activated oncogenes that interfering with downstream signals can lead to apoptosis—and the concept of attacking cancer with therapies targeted not at the cancer cells themselves but at their environment.
How might oncogene addiction or environmental interactions be exploited therapeutically? A better understanding of the signaling pathways that cancer cells employ—both to drive their own growth and in their interactions with their milieu—may provide information critical to interfering with both processes. A Science Perspective by Baselga focuses on protein tyrosine kinases as targets for therapeutic intervention, discussing the use of antibodies and small-molecule tyrosine kinase inhibitors directed against the BCR-ABL fusion oncoprotein, the ErbB2 receptor (also known as Her2), and the epidermal growth factor receptor (EGFR). Gleevec, a tyrosine kinase inhibitor that has been used to treat not only chronic myelogenous leukemia (associated with BCR-ABL) but also gastrointestinal stromal cell tumors related to c-Kit mutation and cancers associated with the platelet-derived growth factor receptor (PDGFR), is the subject of a Perspective by Kaelin in the STKE Archives. A Perspective in the STKE Archives by Olszewski and Grossbard discusses rituximab, the first monoclonal antibody approved in cancer therapy, which is directed against CD20, a calcium channel that may participate in the regulation of lymphocyte activation and proliferation.
Mutations in the tumor suppressor gene p53 and the ras protooncogenes are associated with many human cancers. In an STKE Perspective in this focus issue, Harms and Chen describe recent research indicating that p19ras, a nononcogenic alternatively spliced form of H-Ras, stimulates the transcriptional activation of genes targeted by p73, a tumor suppressor closely related to p53. As the authors note, p73, unlike p53, is rarely mutated in human cancers; thus, understanding its regulation may enable us to control its activity in cancer therapy. The ability of Ras isoforms to transform cells depends on the C terminus, which is also required for membrane targeting. Intriguingly, methotrexate, a well-known antimetabolite that has long been used in chemotherapy, appears to inhibit Ras carboxyl methylation and this may contribute to its antineoplastic activity, as discussed in a Perspective from the STKE Archives by Philips.
Tumor suppressor genes and oncogenes may also be regulated by microRNAs (miRNAs) (see Morris and McManus in the STKE Archives). Indeed, miRNAs, such as those that inhibit the production of Ras, may even be considered as tumor suppressors themselves. Evidence for miRNAs that serve as oncogenes by inhibiting the expression of tumor suppressor genes has not been reported, but this is an intriguing possibility.
Defective regulation of the EGF signaling pathway contributes to many cancers. In an STKE Perspective, Garcia describes how, in renal cell carcinoma, EGFR signaling—even in the absence of EGF—acts through the phosphatidylinositol 3-kinase (PI3K) and Akt pathway to stimulate hypoxia-inducible factors (HIFs) that activate the transcription of target genes that contribute to cancer progression, including vascularization and metastasis. Aberrant EGF signaling may also contribute to various types of epithelial cancers as a consequence of breakdown of epithelial cell tight junctions (see Mullin in the STKE Archives).
Basic research is providing insight into new targets for drug intervention at the gene, RNA, and protein levels. It is not surprising that the ancients saw the devastating biological effects of cancer to represent a force against which they were essentially powerless. But as modern research and medicine continue to define the numerous oncogenes and other causes of cancer in its various forms and the signaling control mechanisms that go awry when cancerous cells invade the body, it is no longer necessary to see this family of diseases as mysterious or in some way beyond scientific and medical intervention. Progress to cures cannot be fast enough, but from this vantage point, we can expect that many forms of the disease will ultimately yield to the relentless pursuit of researchers and clinicians.
Featured in This Focus Issue
Perspectives
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K. L. Harms, X. Chen, p19ras brings a new twist to the regulation of p73 by Mdm2. Sci. STKE 2006, pe24 (2006). [Abstract] [Full Text] [PDF]
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J. A. Garcia, HIFing the brakes: Therapeutic opportunities for treatment of human malignancies. Sci. STKE 2006, pe25 (2006). [Abstract] [Full Text] [PDF]
Virtual Journal
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J. Baselga, Targeting tyrosine kinases in cancer: The second wave. Science 312, 1175–1178 (2006). [Abstract] [Full Text] [PDF]
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H. Varmus, The new era in cancer research. Science 312, 1162–1165 (2006). [Abstract] [Full Text] [PDF]
Related Resources
Editorial Guide
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E. M. Adler, N. R. Gough, Focus issue: A dangerous detour—Cell signaling pathways involved in cancer progression. Sci. STKE 2004, eg2 (2004). [Abstract] [Full Text] [PDF]
Perspectives
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W. G. Kaelin Jr., Gleevec: Prototype or outlier? Sci. STKE 2004, pe12 (2004). [Abstract] [Full Text] [PDF]
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J. P. Morris IV, M. T. McManus, Slowing down the Ras lane: miRNAs as tumor suppressors? Sci. STKE 2005, pe41 (2005). [Abstract] [Full Text] [PDF]
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J. M. Mullin, Epithelial barriers, compartmentation, and cancer. Sci. STKE 2004, pe2 (2004). [Abstract] [Full Text] [PDF]
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A. J. Olszewski, M. L. Grossbard, Empowering targeted therapy: Lessons from rituximab. Sci. STKE 2004, pe30 (2004). [Abstract] [Full Text] [PDF]
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M. R. Philips, Methotrexate and Ras methylation: A new trick for an old drug? Sci. STKE 2004, pe13 (2004). [Abstract] [Full Text] [PDF]
Connections Map
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J. Schlessinger, Epidermal growth factor receptor pathway. Sci. STKE (Connections Map, as seen May 2006), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_14987. [About Connections Map]
