PerspectiveCANCER

Addiction to Oncogenes--the Achilles Heal of Cancer

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Science  05 Jul 2002:
Vol. 297, Issue 5578, pp. 63-64
DOI: 10.1126/science.1073096

A single cancer cell frequently contains mutations in multiple genes, gross chromosomal abnormalities, and widespread changes in its gene expression profile [HN1]. An axiom in cancer research is that the multistage process of tumor formation (1) is driven by progressive acquisition of activating mutations in dominant growth-enhancing genes (oncogenes [HN2]) and inactivating mutations in recessive growth-inhibitory genes (tumor suppressor genes [HN3]) (2). Epigenetic (nonmutational) abnormalities leading to increased or decreased expression of these genes, respectively, are also important for tumorigenesis [HN4] (24). Since the discovery of oncogenes about 20 years ago, more than 100 oncogenes and at least 15 tumor suppressor genes have been identified, and the list keeps growing. Oncogenes and tumor suppressor genes are important not only for cell proliferation but also for cell fate determination [HN5] (differentiation, senescence, and apoptosis), their effects often depending on the type of cell in which they are expressed. Thus, overexpression of a given oncogene can enhance growth in one cell type but inhibit growth or induce apoptosis [HN6] in another (24).

A tantalizing question still under debate is whether an oncogene that is crucial for the initial development of a specific tumor is required for maintaining the malignant phenotype of that tumor. The study by Jain et al. [HN7] on page 102 of this issue (5) addresses this question. By unraveling the molecular circuitry that maintains the biologic properties of cancer cells, we will be better able to predict selective molecular targets for cancer therapy. Jain and colleagues (5) engineered a conditional transgenic mouse to overexpress the myc oncogene [HN8], which induced formation of highly malignant osteogenic sarcoma. They discovered that brief loss of myc overexpression caused the tumor cells to differentiate into mature osteocytes that formed histologically normal bone. It is also intriguing that subsequent reactivation of myc, rather than restoring tumor growth as would be predicted, instead induced apoptosis of the tumor cells.

A one-step remedy.

Cancer cells acquire abnormalities in multiple oncogenes and tumor suppressor genes (A, B, C, and D). Inactivation of a single critical oncogene (A) can induce cancer cells to differentiate into cells with a normal phenotype or to undergo apoptosis. This dependence on (addiction to) A for maintaining the cancer phenotype provides an Achilles heel for tumors that can be exploited in cancer therapy.

CREDIT: KATHARINE SUTLIFF/SCIENCE

These findings are consistent with other data showing that cancer cells are often “addicted to” (that is, physiologically dependent on) the continued activity of specific activated or overexpressed oncogenes for maintenance of their malignant phenotype. For example, Felsher and Bishop (6) showed that transgenic mice expressing the myc oncogene in hematopoietic cells developed malignant T cell leukemias and acute myeloid leukemias. However, when this gene was switched off the leukemic cells underwent proliferative arrest, differentiation, and apoptosis. Pelengaris et al. [HN9] (7) targeted expression of an activatable form of the c-Myc protein to the epidermis of mice and observed formation of angiogenic premalignant skin lesions, which regressed when the c-Myc protein was deactivated. These investigators also discovered that sustained activation of c-Myc is required for maintaining invasive tumors of pancreatic b cells in a transgenic mouse model (8). Transgenic mice expressing an inducible form of the H-ras oncogene [HN10] readily developed melanomas; when the ras gene was switched off the melanomas rapidly underwent apoptosis and regressed (9). In another transgenic model, conditional expression of a Bcr-Abl fusion gene [HN11] resulted in the development of leukemia that eventually killed all of the mice. Yet, when the expression of this gene was switched off, even at advanced stages of disease, the leukemic cells underwent rapid and extensive apoptosis and the mice survived (10). This finding is relevant to recent encouraging clinical trials of a drug (that blocks the tyrosine kinase [HN12] activity of the BCR-ABL protein) for treating patients with chronic myeloid leukemia (CML) [HN13], who carry the Bcr-Abl translocation.

It could be argued that all of these results are peculiar to transgenic mice with leukemia or cancer, because in these models the engineered oncogene plays an unusually potent role in the neoplastic process. Furthermore, in mice there may be fewer additional genetic changes during tumor progression than in humans, since in mice the entire carcinogenic process occurs within months rather than decades [HN14]. However, evidence is accumulating that the phenotype of human cancer cells is also frequently dependent on the continued expression of a single mutated or overexpressed oncogene. Growth of a human pancreatic cancer cell line carrying a mutant K-ras oncogene, but not one carrying normal K-ras [HN15], was inhibited by an antisense K-ras oligonucleotide (11). Moreover, Her-2/neu antisense oligonucleotides [HN16] prevented proliferation of breast cancer cells with amplified Her-2/neu, but had no effect on breast cancer cells that did not overexpress this gene (12).

The cell cycle control gene cyclin D1 [HN17] is frequently overexpressed in a variety of human cancers, often during the early stages of tumor development (3). The continued overexpression of cyclin D1 is critical for maintaining the phenotype of cancer cells. Introduction of antisense cyclin D1 into human esophageal, colon, pancreatic, or squamous carcinoma cells reverted their phenotype toward normal and prevented tumor formation in mice (12). Furthermore, antisense-treated pancreatic cancer cells showed increased sensitivity to chemotherapeutic agents. Intriguingly, the revertant esophageal cancer cell line still expressed moderately high levels of cyclin D1. Thus, the parental cells were “addicted” to cyclin D1, that is, they required a greater amount of cyclin D1 to maintain their malignant phenotype than did other cancer cells that never overexpressed cyclin D1.

Despite these examples, if an activated or overexpressed oncogene exerts its effects by causing genomic instability (thus leading to other critical mutations), then blocking its expression may not reverse the cancer phenotype (5). This appears to be the case in myc-transformed (13) or SV40-transformed (14) fibroblasts. The need for continued activity of a specific oncogene to maintain the cancer phenotype may depend on its functions, the type of cell, and other factors involved in tumor formation (3, 5). For example, in transgenic mice where overexpression of c-myc initiates and maintains invasive mammary carcinomas, a subset of these tumors apparently escape c-Myc dependence by activating endogenous ras oncogenes (15).

Reintroducing a wild-type tumor suppressor gene (encoding, for example, p53, Rb, or APC) into human cancer cells where the respective endogenous gene is inactive usually promotes marked inhibition of growth, induction of apoptosis, and/or inhibition of tumorigenesis in mice (3). These results are also unexpected because, if these cancer cells evolved simply through the stepwise acquisition of several mutations and altered gene expression, then correction of just one mutation should have only a modest inhibitory effect. Thus, some cancer cells seem to be “hypersensitive” to the growth-inhibitory effects of specific tumor suppressor genes (3).

The phenomena of oncogene addiction and tumor suppressor gene hypersensitivity suggest that the multistage process of carcinogenesis is not simply a summation of the individual effects of oncogene activation and tumor suppressor gene inactivation. This is consistent with the fact that the proteins encoded by these genes often play multiple roles in complex and interacting networks that display both positive and negative feedback control. Furthermore, throughout the multistage process, the evolving cancer cell must maintain a state of homeostasis between positive- and negative-acting factors in order to maintain structural integrity, viability, and normal replication. For these reasons, the intracellular circuitry or “wiring diagram” that regulates signal transduction and gene expression in cancer cells is very different, even bizarre, when compared to that of normal cells (3). Because of their bizarre circuitry, cancer cells may be more dependent on the activity of specific oncogenes and more sensitive to the growth-inhibitory effects of specific tumor suppressor genes than normal cells.

The Jain et al. paper and other recent studies present an optimistic message with respect to new approaches for treating cancer. Clinical evidence that oncogene addiction exists is provided by specific antibodies against the Her-2/neu receptor (16) that are being used to successfully treat breast cancer [HN18], and the striking therapeutic effects of the drug imatinib mesylate (STI571) that targets the Bcr-Abl oncogene in CML [HN19] (17). Likewise, the antitumor effects of viral vectors encoding the p53 tumor suppressor gene [HN20] (18) may be due to tumor suppressor hypersensitivity.

The notions of oncogene addiction and tumor suppressor hypersensitivity should help in identifying new cancer drug targets among the myriad changes in gene expression revealed by microarray analyses of human cancers (19). However, pinpointing the most critical targets will also require a more dynamic understanding of cancer cell circuitry. Combinations of drugs will probably still be required for effective cancer therapy. It is likely that administering a single drug will lead to the emergence of drug-resistant mutations (20) or of cell variants whose circuitry is no longer addicted to a specific oncogene or sensitive to a specific tumor suppressor (3).

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

A cancer dictionary is provided by the National Cancer Institute (NCI).

D. Glick's Glossary of Biochemistry and Molecular Biology is provided on the Web by Portland Press.

A genetics glossary is made available by the Biology Teaching Organisation (BTO) of the University of Edinburgh.

The National Human Genome Research Institute (NHGRI) makes available the Talking Glossary of Genetic Terms.

Web Collections, References, and Resource Lists

The Google Web Directory provides links to Internet resources related to molecular biology, cell biology, and cancer.

P. Gannon's Cell & Molecular Biology Online is a collection of annotated links to Internet resources.

MEDLINEplus from the U.S. National Library of Medicine provides links to news and Internet resources on medical topics.

The library of the Karolinska Institutet, Stockholm, Sweden, provides collections of Internet resources on molecular biology and genetics and neoplasms.

Deambulum, an Internet resource for molecular biology, biocomputing, medicine, and biology, is provided by Infobiogen.

The NCI's Cancer.gov Web site provides information about cancer, clinical trails, and cancer research programs, as well as a collection of links to Internet resources related to cancer.

The Guide to Internet Resources for Cancer is maintained by S. Cotterill, Faculty of Medicine Computing Center, University of Newcastle, UK.

Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders made available on the Web by the National Center for Biotechnology Information (NCBI).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is made available by Infobiogen.

CancerGene from the CNRS Laboratoire de Génétique Oncologique, Institut Gustave Roussy, Villejuif, France, is a database of genes involved in cancer.

The NCI's Cancer Genome Anatomy Project has as its goal to determine the gene expression profiles of normal, precancer, and cancer cells. Databases of genes and pathways and other resources are provided.

Online Texts and Lecture Notes

The Companion Web site for the third edition of Biochemistry by Mathews, van Holde, and Ahern offers brief introductions to concepts, molecules, and enzymes.

J. Kimball maintains Kimball's Biology Pages, an online biology textbook and glossary.

NCBI's Genes and Diseases Web presentation includes a section on cancer.

Understanding Cancer is a presented by the NCI News Center.

The Genetics of Cancer is presented by the InTouch Web site.

Cancer Biology Online is an educational resource provided by C. Sackerson, Department of Biology, Iona College, NY.

LectureLinks from the Johns Hopkins School of Medicine makes available lecture notes on neoplasia.

N. Bachman, Biology Department, SUNY College at Oneonta, NY, provides lecture notes for a course on the biology of cancer.

The Clinical Molecular Genetics Society (CMGS) offers tutorials in preparation for the MRC pathology examination in molecular genetics. Lecture notes on cancer genetics are included.

D. Lycan, Department of Biology, Lewis and Clark College, Portland, OR, offers lecture notes for a course on the molecular basis of disease.

R. Keates, Department of Chemistry and Biochemistry, University of Guelph, offers lecture notes for a course on regulation in biological systems.

General Reports and Articles

The fifth edition of Cancer Medicine, edited by R. Bast et al., is available on the NCBI Bookshelf. The first section on the book is devoted to cancer biology.

The January 2000 issue of Hospital Practice had an article by D. Ross titled “Cancer: The emerging molecular biology.” The September 1999 issue had an article by A. Gewirtz titled “The prospects for antisense therapy.”

The December 2000 issue of the Oncologist had an article (reprinted from Mechanisms in Hematology) by E. Israels and L. Israels titled “The cell cycle.” The February 2002 issue had an article by T. Sandal titled “Molecular aspects of the mammalian cell cycle and cancer.”

The May 2000 issue of Carcinogenesis had an article by I. B. Weinstein titled “Disorders in cell circuitry during multistage carcinogenesis: The role of homeostasis” (3).

The 28 August 1998 issue of Science had a review article by G. Evan and T. Littlewood titled “A matter of life and cell death.”

Numbered Hypernotes

1. Cancer cells. H. Lodish et al.'s Molecular Cell Biology, available from the NCBI Bookshelf, has a chapter on cancer. P. McClean, Department of Plant Sciences, North Dakota State University, offers lecture notes on the eukaryotic cell cycle and the genetics of cancer for a genetics course. C. Wilson, Department of Biological Sciences, Southern Illinois University at Edwardsville, offers lecture notes on cancer biology (parts one and two) for a course on human diseases. Lecture notes on neoplasia by R. Mellors, made available by the Weill Education Center of the Weill Medical College of Cornell University, include sections on carcinogenesis and the biological properties of neoplastic cells. The Pathology Department, State University of New York at Stony Brook, makes available lecture notes on cancer invasion and metastasis. The Computer Assisted Teaching System, provided by the Department of Pathology, University of Vermont College of Medicine, offers an introduction to neoplasia and lecture notes on the molecular pathobiology of neoplasia. The 6 December 1996 issue of Science had an article by C. Sherr titled “Cancer cell cycles.”

2. Oncogenes. Understanding Cancer includes section on oncogenes. The Biochemistry companion Web site includes sections on oncogenes and oncogenes and cell signaling. Kimball's Biology Pages offers an introduction to oncogenes. The Genetics of Cancer includes a section on oncogenes and proto-oncogenes. H. Ibelgaufts' Cytokines Online Pathfinder Encyclopaedia (COPE) offers a presentation on oncogenes. F. Lux, Division of Biological and Physical Sciences, Lander University, Greenwood, SC, offers lecture notes on oncogenes and cancer for a molecular biology course. The CMGS pathology course makes available two presentations on oncogenes (lecture one and lecture two). The European School of Genetic Medicine of the European Genetics Foundation offers lecture notes on oncogenes by G. Evan for a course on cancer genetics. I. Kovalchuk, Department of Biological Sciences, University of Lethbridge, Canada, offers lecture notes (in PDF format) on oncogenes and cancer (parts one and two) for a course on advances in genetics, molecular and cell biology.

3. Tumor suppressor genes. Understanding Cancer provides an introduction to tumor suppressor genes. Kimball's Biology Pages includes a presentation on tumor suppressor genes. M. King's Medical Biochemistry Page includes a section on tumor suppressors and cancer. The Genetics of Cancer includes a presentation on tumor suppressor genes. The CMGS pathology course provides lecture notes on tumor suppressor genes.

4. Tumorigenesis. LectureLinks from the Johns Hopkins School of Medicine makes available S. Hamilton's lecture notes and E. Gabrielson's lecture notes on the biology of human tumors. P. Romaniuk, Department of Biochemistry and Microbiology, University of Victoria, Canada, offers lecture notes on cell growth, differentiation, and tumorigenesis for a course on the biochemistry of human health.

5. Cell proliferation and cell fate determination. Cancer Medicine has a chapter on cell proliferation, differentiation, and apoptosis. R. Keates, Department of Chemistry and Biochemistry, University of Guelph, offers lecture notes on cell proliferation and cancer for a course on regulation in biological systems. L. Browder's Dynamic Development makes available presentations on development and cancer. K. Jones, Department of Molecular, Cellular and Developmental Biology, University of Colorado, offers lecture notes on developmental genetics for a course on development on developmental biology.

6. Apoptosis. The Cell Death Society defines apoptosis. The NIH Apoptosis Interest Group offers an introduction to apoptosis. Kimball's Biology Pages offer a presentation apoptosis. L. Browder's Dynamic Development makes available a presentation on apoptosis. J. Knight, Department of Molecular, Cellular and Developmental Biology, University of Colorado, makes available lecture notes on apoptosis for a course on developmental biology. R. Keates, Department of Chemistry and Biochemistry, University of Guelph, offers lecture notes on apoptosis and programmed cell death for a course on regulation in biological systems. The CMGS pathology course makes available two presentations on apoptosis (lecture one and lecture two). The August 1999 issue of the Oncologist had an article on apoptosis by L. Israels and E. Israels (reprinted from Mechanisms in Hematology).

7. M. Jain, C. Arvanitis, C. Sundberg, and D. Felsher are in the Division of Oncology, Stanford University School of Medicine. K. Chu, W. Dewey, E. Leonhardt, and M. Trinh are in the Department of Radiation Oncology, University of California, San Francisco. J. M. Bishop is in the Program in Biological Sciences and at the G. W. Hooper Foundation, University of California, San Francisco. The Bishop Lab has a Web page.

8. myc oncogene. G. Evan, Cancer Research Institute, University of California, San Francisco, offers a research presentation on myc oncogenes. G. Evan's lecture notes on oncogenes include a section on the myc oncogene as well as an overview of the myc oncogene in the glossary provided. H. Ibelgaufts' COPE has a presentation on myc. The GeneCards database has an entry for the gene myc. OMIM has an entry for the myc oncogene. The Atlas of Genetics and Cytogenetics in Oncology and Haematology has an entry for myc. The 15 March 1996 issue of the Biochemical Journal had a review article by K. Ryan and G. Birnie titled “Myc oncogenes: The enigmatic family.” The June 1998 issue of FASEB Journal had a review article by L. Facchini and L. Penna titled “The molecular role of Myc in growth and transformation: Recent discoveries lead to new insights.”

9. Research by Pelengaris et al. S. Pelengaris is at the Molecular Medicine Research Center, Department of Biological Sciences, University of Warwick, UK, and Imperial Cancer Research Fund Laboratories, UK. The University of California, San Francisco, issued a 7 May 2002 news release titled “Provocative insight into what drives cancer” about the 3 May 2000 article in Cell by S. Pelengaris, M. Khan, and G. Evan titled “Suppression of Myc-induced apoptosis in cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression” (8). The Human Genome Laboratory, University of Leuven, Belgium makes available (in PDF format) a review article by S. Pelengaris, B. Rudolph, and T. Littlewood titled “Action of Myc in vivo - proliferation and apoptosis.”

10. H-ras oncogene and the ras family. NCBI's Genes and Diseases offers an introduction to ras oncogene. The Biochemistry companion Web site includes an introduction to ras genes. The Atlas of Genetics and Cytogenetics in Oncology and Haematology provides an article on the ras family. The Cancer Genome Anatomy Project has an entry for H-ras. CancerGene has an entry for H-ras. OMIN has an entry for H-ras. C. Herrmann's group at the Max Planck Institute of Molecular Physiology, offers a presentation on ras.

11. Bcr-Abl fusion gene. CancerGene provides information about Bcr and Abl and their fusion product. The Atlas of Genetics and Cytogenetics in Oncology and Haematology has an entry about the Bcr-Abl fusion. OMIM provides information about the Bcr-Abl fusion gene. The Institute of Hematology and Blood Transfusion, Prague, offers a laboratory reference presentation on the Bcr-Abl fusion gene.

12. Tyrosine kinase is defined in the Biochemistry companion Web site. The CMGS pathology course makes available lecture notes on tyrosine kinases.

13. Chronic myeloid leukemia. NCBI's Genes and Diseases offers an introduction to chronic myeloid leukemia (CML). Kimball's Biology Pages has a presentation chronic myelogenous leukemia (CML). The Atlas of Genetics and Cytogenetics in Oncology and Haematology has an entry on CML. The Leukemia and Lymphoma Society provides a fact sheet about CML. Cancer.gov provides patient and health professional information about CML.

14. Mouse models for cancer. The Emice Web site is provided by the NCI Mouse Models of Human Cancers Consortium. Mouse Genetics: Concepts and Applications by L. Silver is made available on the Web by the Jackson Laboratory, Bar Harbor, ME.

15. An entry for K-ras is included in OMIN. The Atlas of Genetics and Cytogenetics in Oncology and Haematology provides information about the K-ras gene.

16. Antisense and antisense oligonucleotides. Antisense is defined in the NHGRI glossary. The online Columbia Encyclopedia has an entry for antisense. H. Ibelgaufts' COPE offers a presentation on antisense. The Molecula Research Laboratories offers a presentation on antisense oligonucleotides. The April 2002 issue of the Baylor University Medical Center Proceedings had an article (in PDF format) by C. C. Cunningham titled “New modalities in oncology: Antisense oligonucleotides.” E. Wickstrom's Laboratory of Nucleic Acid Therapeutics, Kimmel Cancer Center, Thomas Jefferson University, offers an introduction to antisense therapy. Frontiers in Bioscience makes available an article by G. Sczakiel titled “Theoretical and experimental approaches to design effective antisense oligonucleotides” in a special issue on antisense therapeutics.

17. Cyclin D1. Kimball's Biology Pages provide an introduction to cyclins. Primers in Biology from New Science Press offer a chapter on cyclins by D. Morgan. CancerGene has an entry for cyclin D1. OMIM has an entry for cyclin D1.

18. Antibodies against Her-2/neu receptor. Access Excellence provides an 18 May 1998 article by S. Henahan titled “HER-2/neu vs. breast cancer.” Breastdoctor.com offers a presentation titled “Drug therapy for breast cancer genes: Herceptin antibody therapy.” Cancer.gov offers an information page about Herceptin. The Imaginis Web site offers a presentation on Herceptin and HER2. Genentech's Herceptin Web site offers presentations on the science of HER2 and on the mechanism of action of the monoclonal antibody therapy.

19. Imatinib mesylate (STI571) treatment for CML. CancerBACUP provides a fact sheet about STI571. Access Excellence provides a 21 June 2001 article by S. Henahan titled “Glee for Gleevec.” Cancer.gov provides a resource page on Gleevec (STI571); included is an article from the 5 January 2000 issue of the Journal of the National Cancer Institute titled “Leukemia drug heralds molecularly targeted era.” The Novartis Oncology Division provides information about Gleevec. OncoLink from the University of Pennsylvania Cancer Center makes available an article by B. Somer titled “STI-571 in the treatment of CML: A perspective on this new agent, and its potential future utility.” The FDA Center for Drug Evaluation and Research provides a drug information page for Gleevec (imatinib mesylate). The McLendon Clinical Laboratories, University of North Carolina Hospitals, makes available a slide presentation by F. C. Tessien-Reading titled “STI571 (Gleevec): Molecular targeting in the treatment of CML.”

20. p53 tumor suppressor gene. The BTO genetics glossary defines p53. The Biochemistry companion Web site offers information about p53. NCBI's Genes and Diseases offers an introduction to the p53 tumor suppressor gene. M. Rebhan's HotMolecBase includes a presentation on p53. T. Soussi, Laboratoire de Génotoxicologie des Tumeurs, Institut Curie, Paris, provides a p53 Web site.

21. I. B. Weinstein is in the Department of Genetics and Developmental Biology and at the Herbert Irving Comprehensive Cancer Center, Columbia University.

References

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