Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

RAS oncogenes: weaving a tumorigenic web

Key Points

  • RAS is a GTPase that is frequently mutated in cancer and that affects a variety of cancer-driving processes. Unique properties of RAS isoforms, and of particular activating mutations, may distinctly affect the process of neoplastic conversion in different tissues.

  • RAS drives cellular proliferation by providing both cell-autonomous and non-cell-autonomous cues, which ultimately converge in the transformed cells to promote pro-growth and to inhibit anti-growth signals. RAS-mediated proliferative overdrive may induce replicative stress and activation of DNA damage responses.

  • The suppression of a cell death response by oncogenic RAS is a consequence of a perturbation of homeostatic balance between pro-apoptotic and anti-apoptotic signals. To keep up with the high energy needs of growing cells, the survival of RAS-transformed cells is further aided by metabolic reprogramming towards glycolysis that is mediated by MAPK- and PI3K-dependent regulation of hypoxia-inducible factor 1α (HIF1α).

  • Oncogenic RAS modulates the tumour microenvironment by promoting pro-angiogenic mechanisms and by altering host-mediated immune responses. Transformation by RAS can also promote changes in motility and cellular adhesion, leading to the acquisition of invasive and metastatic properties of cancer cells.

  • Breakthroughs in real-time imaging, computational approaches, high-throughput screening and genetically engineered mouse modelling promise to advance our capacity to integrate the complexity of RAS signalling pathways with the context specificity of their oncogenic activities, undoubtedly aiding the implementation of successful remedial strategies in the clinic.

Abstract

RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Frequency of mutations at G12, G13 and Q61 in RAS isoforms.
Figure 2: RAS effects on proliferation.
Figure 3: RAS effects on apoptosis.
Figure 4: Effect of RAS on energy metabolism in cancer cells: generating macromolecular precursors.
Figure 5: RAS and angiogenesis.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Scheidig, A. J., Burmester, C. & Goody, R. S. The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins. Structure 7, 1311–1324 (1999).

    CAS  PubMed  Google Scholar 

  4. Buhrman, G., Holzapfel, G., Fetics, S. & Mattos, C. Allosteric modulation of Ras positions Q61 for a direct role in catalysis. Proc. Natl Acad. Sci. USA 107, 4931–4936 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheffzek, K. et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333–338 (1997). This article described the first three-dimensional structure of the RAS–RASGAP complex, providing insight into the mechanism of GTP hydrolysis and the structural basis for the oncogenicity of RAS mutants.

    CAS  PubMed  Google Scholar 

  6. Kompier, L. C. et al. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS ONE 5, e13821 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Perentesis, J. P. et al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia 18, 685–692 (2004).

    CAS  PubMed  Google Scholar 

  8. Burmer, G. C., Rabinovitch, P. S. & Loeb, L. A. Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma. Environ. Health Perspect. 93, 27–31 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Capella, G., Cronauer-Mitra, S., Pienado, M. A. & Perucho, M. Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. Environ. Health Perspect. 93, 125–131 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Riely, G. J. et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin. Cancer Res. 14, 5731–5734 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Keohavong, P. et al. Detection of K-ras mutations in lung carcinomas: relationship to prognosis. Clin. Cancer Res. 2, 411–418 (1996).

    CAS  PubMed  Google Scholar 

  12. Andreyev, H. J., Norman, A. R., Cunningham, D., Oates, J. R. & Clarke, P. A. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J. Natl Cancer Inst. 90, 675–684 (1998).

    CAS  PubMed  Google Scholar 

  13. Goody, R. S. et al. Studies on the structure and mechanism of H-ras p21. Philos. Trans. R. Soc. Lond. B Biol. Sci. 336, 3–10; discussion 10–11 (1992).

    CAS  PubMed  Google Scholar 

  14. Al-Mulla, F., Milner-White, E. J., Going, J. J. & Birnie, G. D. Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression. J. Pathol. 187, 433–438 (1999).

    CAS  PubMed  Google Scholar 

  15. Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71–75 (1984).

    CAS  PubMed  Google Scholar 

  16. Edkins, S. et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol. Ther. 5, 928–932 (2006).

    CAS  PubMed  Google Scholar 

  17. Tyner, J. W. et al. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. Blood 113, 1749–1755 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. De Roock, W. et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304, 1812–1820 (2010).

    CAS  PubMed  Google Scholar 

  19. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  Google Scholar 

  20. Karnoub, A. E. & Weinberg, R. A. Ras oncogenes: split personalities. Nature Rev. Mol. Cell Biol. 9, 517–531 (2008).

    CAS  Google Scholar 

  21. Bar-Sagi, D. A Ras by any other name. Mol. Cell Biol. 21, 1441–1443 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).

    CAS  PubMed  Google Scholar 

  23. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    CAS  PubMed  Google Scholar 

  24. Braun, B. S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597–602 (2004).

    CAS  PubMed  Google Scholar 

  25. To, M. D. et al. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nature Genet. 40, 1240–1244 (2008).

    CAS  PubMed  Google Scholar 

  26. Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Genet. 40, 600–608 (2008). In this study, the authors engineered a knock-in system for the endogenous expression of KRAS or NRAS oncogenic mutants to document, for the first time, that the different RAS isoforms have distinct biological functions during tumorigenesis in vivo.

    CAS  PubMed  Google Scholar 

  27. Li, Q. et al. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood 117, 2022–2032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nature Genet. 38, 331–336 (2006). This study identified novel germline activating KRAS mutations in patients with Noonan and cardio-facio-cutaneous syndromes. These mutations lead to milder biochemical activation of RAS than seen in cancer, suggesting why such alterations might be tolerated during development.

    CAS  PubMed  Google Scholar 

  29. Tidyman, W. E. & Rauen, K. A. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Rev. Mol. Med. 10, e37 (2008).

    PubMed  Google Scholar 

  30. Potenza, N. et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 6, 432–437 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Stacey, D. W. & Kung, H. F. Transformation of NIH 3T3 cells by microinjection of Ha-ras p21 protein. Nature 310, 508–511 (1984).

    CAS  PubMed  Google Scholar 

  32. Feramisco, J. R., Gross, M., Kamata, T., Rosenberg, M. & Sweet, R. W. Microinjection of the oncogene form of the human H-ras (T-24) protein results in rapid proliferation of quiescent cells. Cell 38, 109–117 (1984). References 31 and 32 were the first studies to demonstrate that microinjection of purified oncogenic RAS induced dramatic morphological changes and stimulated the proliferation of quiescent cells.

    CAS  PubMed  Google Scholar 

  33. McCarthy, S. A., Samuels, M. L., Pritchard, C. A., Abraham, J. A. & McMahon, M. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev. 9, 1953–1964 (1995).

    CAS  PubMed  Google Scholar 

  34. Gangarosa, L. M. et al. A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells. J. Biol. Chem. 272, 18926–18931 (1997).

    CAS  PubMed  Google Scholar 

  35. Schulze, A., Lehmann, K., Jefferies, H. B., McMahon, M. & Downward, J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 15, 981–994 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Woods, D. et al. Induction of β3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Mol. Cell Biol. 21, 3192–3205 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dajee, M., Tarutani, M., Deng, H., Cai, T. & Khavari, P. A. Epidermal Ras blockade demonstrates spatially localized Ras promotion of proliferation and inhibition of differentiation. Oncogene 21, 1527–1538 (2002).

    CAS  PubMed  Google Scholar 

  38. Filmus, J., Zhao, J. & Buick, R. N. Overexpression of H-ras oncogene induces resistance to the growth-inhibitory action of transforming growth factor β-1 (TGF-β 1) and alters the number and type of TGF-β1 receptors in rat intestinal epithelial cell clones. Oncogene 7, 521–526 (1992).

    CAS  PubMed  Google Scholar 

  39. Zhao, J. & Buick, R. N. Regulation of transforming growth factor β receptors in H-ras oncogene-transformed rat intestinal epithelial cells. Cancer Res. 55, 6181–6188 (1995).

    CAS  PubMed  Google Scholar 

  40. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000).

    CAS  Google Scholar 

  41. Kretzschmar, M., Doody, J., Timokhina, I. & Massague, J. A mechanism of repression of TGFβ/ Smad signaling by oncogenic Ras. Genes Dev. 13, 804–816 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kfir, S. et al. Pathway- and expression level-dependent effects of oncogenic N-Ras: p27(Kip1) mislocalization by the Ral-GEF pathway and Erk-mediated interference with Smad signaling. Mol. Cell Biol. 25, 8239–8250 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Daly, A. C., Vizan, P. & Hill, C. S. Smad3 protein levels are modulated by Ras activity and during the cell cycle to dictate transforming growth factor-β responses. J. Biol. Chem. 285, 6489–6497 (2010).

    CAS  PubMed  Google Scholar 

  44. Stacey, D. W., Watson, T., Kung, H. F. & Curran, T. Microinjection of transforming ras protein induces c-fos expression. Mol. Cell Biol. 7, 523–527 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gutman, A., Wasylyk, C. & Wasylyk, B. Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter. Mol. Cell Biol. 11, 5381–5387 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Urich, M., Senften, M., Shaw, P. E. & Ballmer-Hofer, K. A role for the small GTPase Rac in polyomavirus middle-T antigen-mediated activation of the serum response element and in cell transformation. Oncogene 14, 1235–1241 (1997).

    CAS  PubMed  Google Scholar 

  47. Westwick, J. K. et al. Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases. Proc. Natl Acad. Sci. USA 91, 6030–6034 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Finco, T. S. et al. Oncogenic Ha-Ras-induced signaling activates NF-κB transcriptional activity, which is required for cellular transformation. J. Biol. Chem. 272, 24113–24116 (1997).

    CAS  PubMed  Google Scholar 

  49. Malumbres, M. & Pellicer, A. RAS pathways to cell cycle control and cell transformation. Front. Biosci. 3, D887–D912 (1998).

    CAS  PubMed  Google Scholar 

  50. Filmus, J. et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627–3633 (1994).

    CAS  PubMed  Google Scholar 

  51. Albanese, C. et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 (1995).

    CAS  PubMed  Google Scholar 

  52. Winston, J. T., Coats, S. R., Wang, Y. Z. & Pledger, W. J. Regulation of the cell cycle machinery by oncogenic ras. Oncogene 12, 127–134 (1996).

    CAS  PubMed  Google Scholar 

  53. Liu, J. J. et al. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol. Cell Biol. 15, 3654–3663 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gille, H. & Downward, J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J. Biol. Chem. 274, 22033–22040 (1999).

    CAS  PubMed  Google Scholar 

  55. Westwick, J. K. et al. Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol. Cell Biol. 17, 1324–1335 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Takuwa, N., Fukui, Y. & Takuwa, Y. Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Mol. Cell Biol. 19, 1346–1358 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moodie, S. A., Willumsen, B. M., Weber, M. J. & Wolfman, A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260, 1658–1661 (1993). This is the first publication describing RAF as a direct effector of RAS and providing a structural basis for their interaction.

    CAS  PubMed  Google Scholar 

  58. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Robles, A. I. et al. Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev. 12, 2469–2474 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).

    CAS  PubMed  Google Scholar 

  61. Quelle, D. E. et al. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 7, 1559–1571 (1993).

    CAS  PubMed  Google Scholar 

  62. Resnitzky, D., Gossen, M., Bujard, H. & Reed, S. I. Acceleration of the G1/S. phase transition by expression of cyclins D1 and E with an inducible system. Mol. Cell Biol. 14, 1669–1679 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Rivard, N., Boucher, M. J., Asselin, C. & L'Allemain, G. MAP kinase cascade is required for p27 downregulation and S. phase entry in fibroblasts and epithelial cells. Am. J. Physiol. 277, C652–C664 (1999).

    CAS  PubMed  Google Scholar 

  64. Sa, G. & Stacey, D. W. P27 expression is regulated by separate signaling pathways, downstream of Ras, in each cell cycle phase. Exp. Cell Res. 300, 427–439 (2004).

    CAS  PubMed  Google Scholar 

  65. Leone, G., DeGregori, J., Sears, R., Jakoi, L. & Nevins, J. R. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387, 422–426 (1997).

    CAS  PubMed  Google Scholar 

  66. Pruitt, K., Pestell, R. G. & Der, C. J. Ras inactivation of the retinoblastoma pathway by distinct mechanisms in NIH 3T3 fibroblast and RIE-1 epithelial cells. J. Biol. Chem. 275, 40916–40924 (2000).

    CAS  PubMed  Google Scholar 

  67. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    CAS  PubMed  Google Scholar 

  68. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  69. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  70. Koorstra, J. B. et al. Widespread activation of the DNA damage response in human pancreatic intraepithelial neoplasia. Mod. Pathol. 22, 1439–1445 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    CAS  PubMed  Google Scholar 

  72. Hagag, N., Diamond, L., Palermo, R. & Lyubsky, S. High expression of ras p21 correlates with increased rate of abnormal mitosis in NIH3T3 cells. Oncogene 5, 1481–1489 (1990).

    CAS  PubMed  Google Scholar 

  73. Denko, N., Stringer, J., Wani, M. & Stambrook, P. Mitotic and post mitotic consequences of genomic instability induced by oncogenic Ha-ras. Somat. Cell Mol. Genet. 21, 241–253 (1995). This study provides the first evidence for an association between oncogenic RAS-induced chromosome aberrations and disruption of the mitotic machinery in the process of cellular transformation.

    CAS  PubMed  Google Scholar 

  74. Denko, N. C., Giaccia, A. J., Stringer, J. R. & Stambrook, P. J. The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. Proc. Natl Acad. Sci. USA 91, 5124–5128 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wani, M. A., Denko, N. C. & Stambrook, P. J. Expression of Rap 1 suppresses genomic instability of H-ras transformed mouse fibroblasts. Somat. Cell Mol. Genet. 23, 123–133 (1997).

    CAS  PubMed  Google Scholar 

  76. Knauf, J. A. et al. Oncogenic RAS induces accelerated transition through G2/M and promotes defects in the G2 DNA damage and mitotic spindle checkpoints. J. Biol. Chem. 281, 3800–3809 (2006).

    CAS  PubMed  Google Scholar 

  77. Cox, A. D. & Der, C. J. The dark side of Ras: regulation of apoptosis. Oncogene 22, 8999–9006 (2003).

    CAS  PubMed  Google Scholar 

  78. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999). This study showed that downregulation of HRASG12V leads to apoptosis of tumour cells and host-derived endothelial cells, and consequently, regression of primary and explanted melanomas, indicating the need for RAS in tumour maintenance.

    CAS  PubMed  Google Scholar 

  79. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rosen, K. et al. Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. Curr. Biol. 8, 1331–1334 (1998).

    CAS  PubMed  Google Scholar 

  81. Sulciner, D. J. et al. rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-κB activation. Mol. Cell Biol. 16, 7115–7121 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Joneson, T. & Bar-Sagi, D. Suppression of Ras-induced apoptosis by the Rac GTPase. Mol. Cell Biol. 19, 5892–5901 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mayo, M. W. & Baldwin, A. S. The transcription factor NF-κB: control of oncogenesis and cancer therapy resistance. Biochim. Biophys. Acta 1470, M55–M62 (2000).

    CAS  PubMed  Google Scholar 

  84. Nalca, A., Qiu, S. G., El-Guendy, N., Krishnan, S. & Rangnekar, V. M. Oncogenic Ras sensitizes cells to apoptosis by Par-4. J. Biol. Chem. 274, 29976–29983 (1999).

    CAS  PubMed  Google Scholar 

  85. Ahmed, M. M. et al. Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation. Int. J. Cancer 122, 63–70 (2008).

    CAS  PubMed  Google Scholar 

  86. Kinoshita, T., Yokota, T., Arai, K. & Miyajima, A. Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. Oncogene 10, 2207–2212 (1995).

    CAS  PubMed  Google Scholar 

  87. Wu, L., Nam, Y. J., Kung, G., Crow, M. T. & Kitsis, R. N. Induction of the apoptosis inhibitor ARC by Ras in human cancers. J. Biol. Chem. 285, 19235–19245 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

    CAS  PubMed  Google Scholar 

  89. Fang, X. et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18, 6635–6640 (1999).

    CAS  PubMed  Google Scholar 

  90. Peli, J. et al. Oncogenic Ras inhibits Fas ligand-mediated apoptosis by downregulating the expression of Fas. EMBO J. 18, 1824–1831 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Gazin, C., Wajapeyee, N., Gobeil, S., Virbasius, C. M. & Green, M. R. An elaborate pathway required for Ras-mediated epigenetic silencing. Nature 449, 1073–1077 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Arber, N. Janus faces of ras: anti or pro-apoptotic? Apoptosis 4, 383–388 (1999).

    CAS  PubMed  Google Scholar 

  93. Vermeulen, K., Berneman, Z. N. & Van Bockstaele, D. R. Cell cycle and apoptosis. Cell Prolif. 36, 165–175 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kauffmann-Zeh, A. et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544–548 (1997). Oncogenic RAS can suppress MYC-induced apoptosis in a PKB–AKT-dependent manner and can promote apoptosis through activation of the RAF pathway, thus RAS is capable of eliciting contradictory signals that modulate cell viability.

    CAS  PubMed  Google Scholar 

  95. Kennedy, N. J. et al. Suppression of Ras-stimulated transformation by the JNK signal transduction pathway. Genes Dev. 17, 629–637 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Lei, K. et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol. Cell Biol. 22, 4929–4942 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Bivona, T. G. et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481–493 (2006).

    CAS  PubMed  Google Scholar 

  98. Richter, A. M., Pfeifer, G. P. & Dammann, R. H. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim. Biophys. Acta 1796, 114–128 (2009).

    CAS  PubMed  Google Scholar 

  99. Vos, M. D., Ellis, C. A., Bell, A., Birrer, M. J. & Clark, G. J. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J. Biol. Chem. 275, 35669–35672 (2000).

    CAS  PubMed  Google Scholar 

  100. Khokhlatchev, A. et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253–265 (2002).

    CAS  PubMed  Google Scholar 

  101. Patra, S. K. Ras regulation of DNA-methylation and cancer. Exp. Cell Res. 314, 1193–1201 (2008).

    CAS  PubMed  Google Scholar 

  102. Dammann, R. et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nature Genet. 25, 315–319 (2000).

    CAS  PubMed  Google Scholar 

  103. Dammann, R. et al. The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol. Histopathol. 20, 645–663 (2005).

    CAS  PubMed  Google Scholar 

  104. Burbee, D. G. et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J. Natl Cancer Inst. 93, 691–699 (2001).

    CAS  PubMed  Google Scholar 

  105. Fullwood, P. et al. Detailed genetic and physical mapping of tumor suppressor loci on chromosome 3p in ovarian cancer. Cancer Res. 59, 4662–4667 (1999).

    CAS  PubMed  Google Scholar 

  106. Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  Google Scholar 

  108. Mathupala, S. P., Heese, C. & Pedersen, P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).

    CAS  PubMed  Google Scholar 

  109. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA 102, 8573–8578 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Foster, K. G. & Fingar, D. C. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J. Biol. Chem. 285, 14071–14077 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen, C., Pore, N., Behrooz, A., Ismail-Beigi, F. & Maity, A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol. Chem. 276, 9519–9525 (2001).

    CAS  PubMed  Google Scholar 

  113. Blum, R., Jacob-Hirsch, J., Amariglio, N., Rechavi, G. & Kloog, Y. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1α, causing glycolysis shutdown and cell death. Cancer Res. 65, 999–1006 (2005).

    CAS  PubMed  Google Scholar 

  114. Flier, J. S., Mueckler, M. M., Usher, P. & Lodish, H. F. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235, 1492–1495 (1987).

    CAS  PubMed  Google Scholar 

  115. Dang, C. V. & Semenza, G. L. Oncogenic alterations of metabolism. Trends Biochem. Sci. 24, 68–72 (1999).

    CAS  PubMed  Google Scholar 

  116. Shaw, R. J. Glucose metabolism and cancer. Curr. Opin. Cell Biol. 18, 598–608 (2006).

    CAS  PubMed  Google Scholar 

  117. Semenza, G. L. Hypoxia and cancer. Cancer Metastasis Rev. 26, 223–224 (2007).

    CAS  PubMed  Google Scholar 

  118. Kole, H. K., Resnick, R. J., Van Doren, M. & Racker, E. Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch. Biochem. Biophys. 286, 586–590 (1991).

    CAS  PubMed  Google Scholar 

  119. Ramanathan, A., Wang, C. & Schreiber, S. L. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl Acad. Sci. USA 102, 5992–5997 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chiaradonna, F. et al. Ras-dependent carbon metabolism and transformation in mouse fibroblasts. Oncogene 25, 5391–5404 (2006). This paper demonstrates that the known sensitivity of RAS-transformed cells to glucose levels is a consequence of RAS-induced global transcriptomic changes in genes associated with the shift of carbon metabolism towards glycolysis.

    CAS  PubMed  Google Scholar 

  121. Yalcin, A., Telang, S., Clem, B. & Chesney, J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases in cancer. Exp. Mol. Pathol. 86, 174–179 (2009).

    CAS  PubMed  Google Scholar 

  122. Rabinowitz, J. D. & White, E. Autophagy and metabolism. Science 330, 1344–1348 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Lock, R. et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22, 165–178 (2010).

    PubMed  Google Scholar 

  125. Kim, M. J. et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J. Biol. Chem. 286, 12924–12932 (2011). References 123–125 show that RAS-mediated upregulation of autophagy increases cell viability and tumorigenic potential through facilitation of glycolysis and mitochondrial metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Folkman, J., Watson, K., Ingber, D. & Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).

    CAS  PubMed  Google Scholar 

  127. Rak, J. et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55, 4575–4580 (1995).

    CAS  PubMed  Google Scholar 

  128. Rak, J. & Yu, J. L. Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”. Semin. Cancer Biol. 14, 93–104 (2004).

    CAS  PubMed  Google Scholar 

  129. Kranenburg, O., Gebbink, M. F. & Voest, E. E. Stimulation of angiogenesis by Ras proteins. Biochim. Biophys. Acta 1654, 23–37 (2004).

    CAS  PubMed  Google Scholar 

  130. Ancrile, B. B., O'Hayer, K. M. & Counter, C. M. Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics. Mol. Interv. 8, 22–27 (2008).

    CAS  PubMed  Google Scholar 

  131. Tokunaga, T. et al. Ribozyme-mediated inactivation of mutant K-ras oncogene in a colon cancer cell line. Br. J. Cancer 83, 833–839 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Jung, F. et al. Hypoxic induction of the hypoxia-inducible factor is mediated via the adaptor protein Shc in endothelial cells. Circ. Res. 91, 38–45 (2002).

    CAS  PubMed  Google Scholar 

  133. Blancher, C., Moore, J. W., Robertson, N. & Harris, A. L. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1αl, HIF-2α, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway. Cancer Res. 61, 7349–7355 (2001).

    CAS  PubMed  Google Scholar 

  134. Lee, E., Yim, S., Lee, S. K. & Park, H. Two transactivation domains of hypoxia-inducible factor-1α regulated by the MEK-1/p42/p44 MAPK pathway. Mol. Cells 14, 9–15 (2002).

    CAS  PubMed  Google Scholar 

  135. Richard, D. E., Berra, E., Gothie, E., Roux, D. & Pouyssegur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 (1999).

    CAS  PubMed  Google Scholar 

  136. Tsujii, M. et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93, 705–716 (1998).

    CAS  PubMed  Google Scholar 

  137. Dormond, O., Foletti, A., Paroz, C. & Ruegg, C. NSAIDs inhibit α V β 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nature Med. 7, 1041–1047 (2001).

    CAS  PubMed  Google Scholar 

  138. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004). This study demonstrates that oncogenic RAS-mediated production of the cytokine IL-8 has a vital role in neo-angiogenesis and tumour growth by instigating inflammatory reactions in the neoplastic microenvironment.

    CAS  PubMed  Google Scholar 

  139. Borrello, M. G., Degl'Innocenti, D. & Pierotti, M. A. Inflammation and cancer: the oncogene-driven connection. Cancer Lett. 267, 262–270 (2008).

    CAS  PubMed  Google Scholar 

  140. Feng, Y., Santoriello, C., Mione, M., Hurlstone, A. & Martin, P. Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoS Biol. 8, e1000562 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    CAS  PubMed  Google Scholar 

  142. Engelse, M. A., Hanemaaijer, R., Koolwijk, P. & van Hinsbergh, V. W. The fibrinolytic system and matrix metalloproteinases in angiogenesis and tumor progression. Semin. Thromb. Hemost. 30, 71–82 (2004).

    CAS  PubMed  Google Scholar 

  143. Testa, J. E., Medcalf, R. L., Cajot, J. F., Schleuning, W. D. & Sordat, B. Urokinase-type plasminogen activator biosynthesis is induced by the EJ-Ha-ras oncogene in CL26 mouse colon carcinoma cells. Int. J. Cancer 43, 816–822 (1989).

    CAS  PubMed  Google Scholar 

  144. Gum, R. et al. Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J. Biol. Chem. 271, 10672–10680 (1996).

    CAS  PubMed  Google Scholar 

  145. Pepper, M. S. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler. Thromb. Vasc. Biol. 21, 1104–1117 (2001).

    CAS  PubMed  Google Scholar 

  146. Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator. Nature Rev. Mol. Cell Biol. 3, 932–943 (2002).

    CAS  Google Scholar 

  147. Carmeliet, P. & Collen, D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb. Res. 91, 255–285 (1998).

    CAS  PubMed  Google Scholar 

  148. Brodsky, S. et al. Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. Am. J. Physiol. Heart Circ. Physiol. 281, H1784–H1792 (2001).

    CAS  PubMed  Google Scholar 

  149. Zabrenetzky, V., Harris, C. C., Steeg, P. S. & Roberts, D. D. Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines. Int. J. Cancer 59, 191–195 (1994).

    CAS  PubMed  Google Scholar 

  150. Rak, J. et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res. 60, 490–498 (2000).

    CAS  PubMed  Google Scholar 

  151. Volpert, O. V. et al. Inhibition of angiogenesis by thrombospondin-2. Biochem. Biophys. Res. Commun. 217, 326–332 (1995).

    CAS  PubMed  Google Scholar 

  152. Lawler, J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J. Cell. Mol. Med. 6, 1–12 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Maudsley, D. J., Bateman, W. J. & Morris, A. G. Reduced stimulation of helper T cells by Ki-ras transformed cells. Immunology 72, 277–281 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lohmann, S., Wollscheid, U., Huber, C. & Seliger, B. Multiple levels of MHC class I down-regulation by ras oncogenes. Scand. J. Immunol. 43, 537–544 (1996).

    CAS  PubMed  Google Scholar 

  155. Seliger, B. et al. Suppression of MHC class I antigens in oncogenic transformants: association with decreased recognition by cytotoxic T lymphocytes. Exp. Hematol. 24, 1275–1279 (1996).

    CAS  PubMed  Google Scholar 

  156. Ehrlich, T. et al. The effect of H-ras expression on tumorigenicity and immunogenicity of Balb/c 3T3 fibroblasts. Immunol. Lett. 39, 3–8 (1993).

    CAS  PubMed  Google Scholar 

  157. Testorelli, C. et al. Dacarbazine-induced immunogenicity of a murine leukemia is attenuated in cells transfected with mutated K-ras gene. J. Exp. Clin. Cancer Res. 16, 15–22 (1997).

    CAS  PubMed  Google Scholar 

  158. Weijzen, S., Velders, M. P. & Kast, W. M. Modulation of the immune response and tumor growth by activated Ras. Leukemia 13, 502–513 (1999).

    CAS  PubMed  Google Scholar 

  159. Sers, C. et al. Down-regulation of HLA Class I and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells. Int. J. Cancer 125, 1626–1639 (2009).

    CAS  PubMed  Google Scholar 

  160. Seliger, B. et al. Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. Eur. J. Immunol. 28, 122–133 (1998).

    CAS  PubMed  Google Scholar 

  161. Delp, K., Momburg, F., Hilmes, C., Huber, C. & Seliger, B. Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin. Bone Marrow Transplant 25 (Suppl. 2), S88–S95 (2000).

    PubMed  Google Scholar 

  162. Clark, C. E., Beatty, G. L. & Vonderheide, R. H. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 279, 1–7 (2009).

    CAS  PubMed  Google Scholar 

  163. Kubuschok, B. et al. Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer. Clin. Cancer Res. 12, 1365–1372 (2006).

    CAS  PubMed  Google Scholar 

  164. Fossum, B., Olsen, A. C., Thorsby, E. & Gaudernack, G. CD8+ T cells from a patient with colon carcinoma, specific for a mutant p21-Ras-derived peptide (Gly13-->Asp), are cytotoxic towards a carcinoma cell line harbouring the same mutation. Cancer Immunol. Immunother. 40, 165–172 (1995).

    CAS  PubMed  Google Scholar 

  165. Qin, H. et al. CD4+ T-cell immunity to mutated ras protein in pancreatic and colon cancer patients. Cancer Res. 55, 2984–2987 (1995).

    CAS  PubMed  Google Scholar 

  166. Gjertsen, M. K. & Gaudernack, G. Mutated Ras peptides as vaccines in immunotherapy of cancer. Vox Sang 74 (Suppl. 2), 489–495 (1998).

    CAS  PubMed  Google Scholar 

  167. DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).

    CAS  PubMed  Google Scholar 

  169. Tran Thang, N. N. et al. Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development. Cancer Res. 70, 4829–4839 (2010).

    PubMed  Google Scholar 

  170. Granville, C. A. et al. A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS ONE 4, e5061 (2009).

    PubMed  PubMed Central  Google Scholar 

  171. Ji, H. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105–2112 (2006).

    CAS  PubMed  Google Scholar 

  172. Soudja, S. M. et al. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res. 70, 3515–3525 (2010).

    CAS  PubMed  Google Scholar 

  173. Grunert, S., Jechlinger, M. & Beug, H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nature Rev. Mol. Cell Biol. 4, 657–665 (2003).

    Google Scholar 

  174. Smakman, N., Borel Rinkes, I. H., Voest, E. E. & Kranenburg, O. Control of colorectal metastasis formation by K-Ras. Biochim. Biophys. Acta 1756, 103–114 (2005).

    CAS  PubMed  Google Scholar 

  175. Muschel, R. J., Williams, J. E., Lowy, D. R. & Liotta, L. A. Harvey ras induction of metastatic potential depends upon oncogene activation and the type of recipient cell. Am. J. Pathol. 121, 1–8 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Bondy, G. P., Wilson, S. & Chambers, A. F. Experimental metastatic ability of H-ras-transformed NIH3T3 cells. Cancer Res. 45, 6005–6009 (1985).

    CAS  PubMed  Google Scholar 

  177. Huber, M. A., Kraut, N. & Beug, H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 17, 548–558 (2005).

    CAS  PubMed  Google Scholar 

  178. Schmidt, C. R. et al. E-cadherin is regulated by the transcriptional repressor SLUG during Ras-mediated transformation of intestinal epithelial cells. Surgery 138, 306–312 (2005).

    PubMed  Google Scholar 

  179. Horiguchi, K. et al. Role of Ras signaling in the induction of snail by transforming growth factor-β. J. Biol. Chem. 284, 245–253 (2009).

    CAS  PubMed  Google Scholar 

  180. Oft, M., Heider, K. H. & Beug, H. TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol. 8, 1243–1252 (1998).

    CAS  PubMed  Google Scholar 

  181. Fujimoto, K., Sheng, H., Shao, J. & Beauchamp, R. D. Transforming growth factor-β1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells. Exp. Cell Res. 266, 239–249 (2001).

    CAS  PubMed  Google Scholar 

  182. Giehl, K. Oncogenic Ras in tumour progression and metastasis. Biol. Chem. 386, 193–205 (2005).

    CAS  PubMed  Google Scholar 

  183. Plantefaber, L. C. & Hynes, R. O. Changes in integrin receptors on oncogenically transformed cells. Cell 56, 281–290 (1989).

    CAS  PubMed  Google Scholar 

  184. Danen, E. H. & Yamada, K. M. Fibronectin, integrins, and growth control. J. Cell Physiol. 189, 1–13 (2001).

    CAS  PubMed  Google Scholar 

  185. Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004).

    CAS  Google Scholar 

  186. Schramm, K. et al. Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells. Int. J. Cancer 87, 155–164 (2000).

    CAS  PubMed  Google Scholar 

  187. Pollock, C. B., Shirasawa, S., Sasazuki, T., Kolch, W. & Dhillon, A. S. Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells. Cancer Res. 65, 1244–1250 (2005).

    CAS  PubMed  Google Scholar 

  188. Campbell, P. M. & Der, C. J. Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin. Cancer Biol. 14, 105–114 (2004).

    CAS  PubMed  Google Scholar 

  189. Frisch, S. M. & Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994). This study documents the capacity of oncogenic HRAS to abrogate the apoptotic barrier to malignancy initiated by matrix detachment.

    CAS  PubMed  Google Scholar 

  190. Zhang, Y. A., Nemunaitis, J., Scanlon, K. J. & Tong, A. W. Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. Gene Ther. 7, 2041–2050 (2000).

    CAS  PubMed  Google Scholar 

  191. Rosen, K. et al. Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells. J. Cell Biol. 149, 447–456 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Zondag, G. C. et al. Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J. Cell Biol. 149, 775–782 (2000). These authors show that oncogenic RAS signalling is capable of downregulating the activity of RAC and promoting epithelial-to-mesenchymal transition through enhancing signalling through RHO GTPase.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Gupta, S., Plattner, R., Der, C. J. & Stanbridge, E. J. Dissection of Ras-dependent signaling pathways controlling aggressive tumor growth of human fibrosarcoma cells: evidence for a potential novel pathway. Mol. Cell Biol. 20, 9294–9306 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Quinlan, M. P. Rac regulates the stability of the adherens junction and its components, thus affecting epithelial cell differentiation and transformation. Oncogene 18, 6434–6442 (1999).

    CAS  PubMed  Google Scholar 

  195. Braga, V. M., Betson, M., Li, X. & Lamarche-Vane, N. Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes. Mol. Biol. Cell 11, 3703–3721 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).

    Google Scholar 

  197. Turley, E. A., Veiseh, M., Radisky, D. C. & Bissell, M. J. Mechanisms of disease: epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression? Nature Clin. Pract. Oncol. 5, 280–290 (2008).

    CAS  Google Scholar 

  198. Rocks, O., Peyker, A. & Bastiaens, P. I. Spatio-temporal segregation of Ras signals: one ship, three anchors, many harbors. Curr. Opin. Cell Biol. 18, 351–357 (2006).

    CAS  PubMed  Google Scholar 

  199. Henis, Y. I., Hancock, J. F. & Prior, I. A. Ras acylation, compartmentalization and signaling nanoclusters (Review). Mol. Membr. Biol. 26, 80–92 (2009).

    CAS  PubMed  Google Scholar 

  200. Manning, B. D. & Cantley, L. C. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans. 31, 573–578 (2003).

    CAS  PubMed  Google Scholar 

  201. Ballif, B. A. et al. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl Acad. Sci. USA 102, 667–672 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

    CAS  PubMed  Google Scholar 

  203. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489–13494 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Esteve-Puig, R., Canals, F., Colome, N., Merlino, G. & Recio, J. A. Uncoupling of the LKB1-AMPKα energy sensor pathway by growth factors and oncogenic BRAF. PLoS ONE 4, e4771 (2009).

    PubMed  PubMed Central  Google Scholar 

  205. Vizan, P. et al. K-ras codon-specific mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] fibroblasts. Cancer Res. 65, 5512–5515 (2005).

    CAS  PubMed  Google Scholar 

  206. Milanini, J., Vinals, F., Pouyssegur, J. & Pages, G. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J. Biol. Chem. 273, 18165–18172 (1998).

    CAS  PubMed  Google Scholar 

  207. Milanini-Mongiat, J., Pouyssegur, J. & Pages, G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J. Biol. Chem. 277, 20631–20639 (2002).

    CAS  PubMed  Google Scholar 

  208. Merchant, J. L., Du, M. & Todisco, A. Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochem. Biophys. Res. Commun. 254, 454–461 (1999).

    CAS  PubMed  Google Scholar 

  209. Oikawa, T. ETS transcription factors: possible targets for cancer therapy. Cancer Sci. 95, 626–633 (2004).

    CAS  PubMed  Google Scholar 

  210. White, F. C., Benehacene, A., Scheele, J. S. & Kamps, M. VEGF mRNA is stabilized by ras and tyrosine kinase oncogenes, as well as by UV radiation—evidence for divergent stabilization pathways. Growth Factors 14, 199–212 (1997).

    CAS  PubMed  Google Scholar 

  211. Berra, E., Pages, G. & Pouyssegur, J. MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev. 19, 139–145 (2000).

    CAS  PubMed  Google Scholar 

  212. Kevil, C. G. et al. Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis. Int. J. Cancer 65, 785–790 (1996).

    CAS  PubMed  Google Scholar 

  213. Mamane, Y. et al. eIF4E–from translation to transformation. Oncogene 23, 3172–3179 (2004).

    CAS  PubMed  Google Scholar 

  214. Xie, W. & Herschman, H. R. Transcriptional regulation of prostaglandin synthase 2 gene expression by platelet-derived growth factor and serum. J. Biol. Chem. 271, 31742–31748 (1996).

    CAS  PubMed  Google Scholar 

  215. Sheng, H. et al. Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J. Biol. Chem. 273, 22120–22127 (1998).

    CAS  PubMed  Google Scholar 

  216. Reddy, S. T., Wadleigh, D. J. & Herschman, H. R. Transcriptional regulation of the cyclooxygenase-2 gene in activated mast cells. J. Biol. Chem. 275, 3107–3113 (2000).

    CAS  PubMed  Google Scholar 

  217. Subbaramaiah, K., Norton, L., Gerald, W. & Dannenberg, A. J. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J. Biol. Chem. 277, 18649–18657 (2002).

    CAS  PubMed  Google Scholar 

  218. Lengyel, E., Stepp, E., Gum, R. & Boyd, D. Involvement of a mitogen-activated protein kinase signaling pathway in the regulation of urokinase promoter activity by c-Ha-ras. J. Biol. Chem. 270, 23007–23012 (1995).

    CAS  PubMed  Google Scholar 

  219. Jiang, Y. & Muschel, R. J. Regulation of matrix metalloproteinase-9 (MMP-9) by translational efficiency in murine prostate carcinoma cells. Cancer Res. 62, 1910–1914 (2002).

    CAS  PubMed  Google Scholar 

  220. Shapiro, R. L. et al. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res. 56, 3597–3604 (1996).

    CAS  PubMed  Google Scholar 

  221. Wolthuis, R. M. & Bos, J. L. Ras caught in another affair: the exchange factors for Ral. Curr. Opin. Genet. Dev. 9, 112–117 (1999).

    CAS  PubMed  Google Scholar 

  222. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001). This paper was the first to feature conditional activation of an endogenous KRASG12D allele in an animal model, and showed that this is sufficient to drive progression from pulmonary hyperplasia to adenocarcinoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    CAS  PubMed  Google Scholar 

  224. Chan, I. T. et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528–538 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Brembeck, F. H. et al. The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 63, 2005–2009 (2003).

    CAS  PubMed  Google Scholar 

  226. Mo, L. et al. Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J. Clin. Invest. 117, 314–325 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Vitale-Cross, L., Amornphimoltham, P., Fisher, G., Molinolo, A. A. & Gutkind, J. S. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis. Cancer Res. 64, 8804–8807 (2004).

    CAS  PubMed  Google Scholar 

  228. Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984).

    CAS  PubMed  Google Scholar 

  229. Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55–57 (2000).

    CAS  PubMed  Google Scholar 

  230. Seidler, B. et al. A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors. Proc. Natl Acad. Sci. USA 105, 10137–10142 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lungcancer in mice. Nature 410, 1111–1116 (2001). This study featured activation of oncogenic KRAS transgene by spontaneous somatic recombination events in the whole animal, resulting in the acquisition of a broad range of tumour types.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work was supported by the US National Institutes of Health Grants CA055360 and GM078266 (D.B.-S.), the Ruth L. Kirschstein National Service Award 1F32CA13922 (E.G.) and the Irvington Institute Fellowship Program of the Cancer Research Institute (Y.P.-G). The authors would like to apologize to all their colleagues whose work was not included owing to space constraints.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dafna Bar-Sagi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Glossary

Guanine nucleotide exchange factors

(GEFs). Proteins that promote the exchange of GDP for GTP on a GTPase, thus facilitating its activation.

GTPase-activating proteins

(GAPs). Accelerate the hydrolysis of GTP to GDP, leading to an increase in the proportion of GDP-bound GTPase molecules and a consequent reduction in their activity.

van der Waals bonds

The sum of non-covalent attractive or repulsive forces between atoms or molecules generated by fluctuations in dipole polarization.

Noonan syndrome

A fairly common autosomal dominant congenital condition that manifests with mild mental retardation, heart defects, short stature and impaired blood clotting. Children with Noonan syndrome are often predisposed to juvenile myelomonocytic leukaemia.

Cardio-facio-cutaneous syndrome

Individuals with this disorder usually have distinctive malformations of the craniofacial area, including an unusually large head. Germline mutations in KRAS, BRAF, MEK1 and MEK2 are found in these patients.

Costello syndrome

This is a rare genetic disorder associated with developmental delay, mental retardation, and heart and facial defects. Patients with Costello syndrome are predisposed to rhabdomyosarcoma.

G0 phase

A specialized, non-dividing (or resting) state of cellular quiescence.

DNA damage response

(DDR). Cellular responses to DNA damage, involving a cascade of signalling pathways that coordinate cell cycle arrest and DNA repair.

Apoptosis

The process of programmed cell death that can be initiated by either extracellular or intracellular mediators in response to a predefined developmental programme or in response to cellular stress.

Extracellular matrix

(ECM). A collection of proteins, such as collagen and laminin, and carbohydrates, that provides vital structural and signalling support to cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11, 761–774 (2011). https://doi.org/10.1038/nrc3106

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3106

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer