Concepts, Challenges and Perspectives in Cancer Research

  • Jianren Gu
  • Wenxin Qin
  • Zhigang Zhang


Cancer is one of the most fatal diseases in the world. It caused almost 12% of all deaths in women and 14% in men in 2004, only next to cardiovascular diseases, infectious and parasitic diseases. After a century of combat against cancer, the outcome of cancer treatment has noticeably improved. For example, early detection, diagnosis and treatment of cancer of the cervix and breast have lead to a high cure rate for these cancer patients in the early stage of the disease. In the past decade, the progress in innovation in radiotherapy equipment and the discovery of targeted chemotherapeutic drugs have noticeably improved the survival rate for certain types of cancer at the early or middle stages, such as some gastric, colorectal, nasopharyngeal, esophageal cancers and some histopathological types of malignant lymphoma. However, in spite of these achievements, the overall survival rate for cancer, particularly regarding hepatic cancer, pancreatic and small cell lung cancer and others has still not significantly increased. Therefore, we have to pay serious attention to the basic concepts of cancer biology, especially the mechanism of carcinogenesis, cancer development and its progression, to achieve the goal of 3P cancer medicine: the prevention (primary and secondary); the prediction of cancer as well as its clinical outcome, particularly metastasis; and the personalized treatment of cancer.


Cancer Stem Cell Tumor Microenvironment Stellate Cell Human Melanoma Cell Stromal Fibroblast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. [1]
    World Health Organization. The global burden of disease 2004 update. WHO Press, Part 2: 8.Google Scholar
  2. [2]
    Liotta L A, Kohn E C. The microenvironment of the tumor-host interface. Nature, 2001, 411: 375–379.PubMedCrossRefGoogle Scholar
  3. [3]
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer, 2006, 6: 392–401.PubMedCrossRefGoogle Scholar
  4. [4]
    Pollard J W, Joyce J A. Microenviromental regulation of metastasis. Nat Rev Cancer, 2009, 9: 239–252.PubMedCrossRefGoogle Scholar
  5. [5]
    Delinassios J G, Kottaridis S D, Garas J. Uncontrolled growth of tumor stromal fibroblasts in vitro. Exp Cell Biol, 1983, 51: 201–209.PubMedGoogle Scholar
  6. [6]
    Delinassios J G. Prolonged in vitro maintenance of human diploid fibroblasts on a new tissue-culture medium. Exp Cell Biol, 1983, 51: 315–321.Google Scholar
  7. [7]
    Orimo A, Gupta P B, Sgroi D C, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005, 121: 335–348.PubMedCrossRefGoogle Scholar
  8. [8]
    Sugimoto H, Mundel T M, Kieran M W, et al. Identification of fibroblast heterogeneity in the tumor microenviroment. Cancer Biol Ther, 2006, 5: 1640–1646.PubMedCrossRefGoogle Scholar
  9. [9]
    Ostman A, Augsten M. Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr Opin Genet Dev, 2009, 19: 67–73.PubMedCrossRefGoogle Scholar
  10. [10]
    Orimo A, Weinberg R A. Stromal fibroblasts in cancer. Cell Cycle, 2006, 5: 1597–1601.PubMedCrossRefGoogle Scholar
  11. [11]
    Hu M, Yao J, Cai L, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet, 2005, 37: 899–905.PubMedCrossRefGoogle Scholar
  12. [12]
    Hanson J A, Gillespie J W, Grover A, et al. Gene promoter methylation in prostate tumor-associated stromal cells. J Natl Cancer Inst, 2006, 98: 255–261.PubMedCrossRefGoogle Scholar
  13. [13]
    Patocs A, Zhang L, Xu Y, et al. Breast-cancer stromal cells with TP53 mutations and nodal metastasis. N Eng J Med, 2007, 357: 2543–2551.CrossRefGoogle Scholar
  14. [14]
    Weber F, Wu Y, Zhang L, et al. Microenviromental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma. JAMA, 2007, 297: 187–195.PubMedCrossRefGoogle Scholar
  15. [15]
    Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenviroment in breast cancer. Cancer Cell, 2004, 6: 17–32.PubMedCrossRefGoogle Scholar
  16. [16]
    Qiu W, Hu M, Sridhar A, et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinoma. Nat Genet, 2008, 40: 650–655.PubMedCrossRefGoogle Scholar
  17. [17]
    Bhowmick N A, Chytil A, Plieth D, et al. TGF-ß signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science, 2004, 303: 848–851.PubMedCrossRefGoogle Scholar
  18. [18]
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer, 2006, 6: 392–401.PubMedCrossRefGoogle Scholar
  19. [19]
    Radisky D C, Kenny P A, Bissell M J. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem, 2007, 101: 830–839.PubMedCrossRefGoogle Scholar
  20. [20]
    Le Bitoux M A, Stamenkovic I. Tumor-host interactions: the role of inflammation. Histochem and Cell Biol, 2008, 130: 1079–1090.CrossRefGoogle Scholar
  21. [21]
    Olsson A K, Dimberg A, Kreuger J, et al. VEGF receptor signaling in control of vascular function. Nature Reviews, 2006, 7: 359–371.PubMedCrossRefGoogle Scholar
  22. [22]
    Folkman J. In: Holland JF, et al. (eds). Cancer Medicine. Decker, Ontario, Canada, 2000: 132–152.Google Scholar
  23. [23]
    Hanahan D, Weinberg R A. The hallmarks of cancer. Cell, 2000, 100: 57–70.PubMedCrossRefGoogle Scholar
  24. [24]
    Zumsteg A, Christofori G. Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr Opin Oncol, 2008, 21: 60–70.CrossRefGoogle Scholar
  25. [25]
    Coussens L M, Werb Z. Inflammation and cancer. Nature, 2002, 420: 860–867.PubMedCrossRefGoogle Scholar
  26. [26]
    Lin E Y, Pollard J W. Macrophages: modulators of breast cancer progression. Novartis Foundation Symposium, 2004, 256: 158–168.PubMedCrossRefGoogle Scholar
  27. [27]
    Denys H, Braems G, Lambein K, et al. The extracellular matrix regulates cancer progression and therapy response: implications for prognosis and treatment. Curr Pharm Des, 2009, 15: 1373–1384.PubMedCrossRefGoogle Scholar
  28. [28]
    Angeli F, Koumakis G, Chen M C, et al. Role of stromal fibroblasts in cancer: promoting or impeding? Tumor Biol, 2009, 30: 109–120.CrossRefGoogle Scholar
  29. [29]
    Hewitt R E, Powe D G, Carter I, et al. Desmoplasia and its relevance to colorectal tumor invasion. Int J Cancer, 1993, 53: 62–69.PubMedCrossRefGoogle Scholar
  30. [30]
    Pupa S M, Menard S, Forti S, et al. New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol, 2002, 192: 259–267.PubMedCrossRefGoogle Scholar
  31. [31]
    Bellon G, Martiny L, Robinet A. Matrix metalloproteinases and matrikines in angiogenesis. Crit Rev Oncol Hematol, 2004, 49: 203–220.PubMedCrossRefGoogle Scholar
  32. [32]
    Maquart F X, Pasco S, Ramont L, et al. An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity. Implication in tumor invasion. Crit Rev Oncol Hematol, 2004, 49: 199–202.PubMedCrossRefGoogle Scholar
  33. [33]
    Hynes R O. The extracellular matrix: not just pretty fibrils. Science, 2009, 326: 1216–1219.PubMedCrossRefGoogle Scholar
  34. [34]
    Levental K R, Yu H, Kass L, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 2009, 139: 891–906.PubMedCrossRefGoogle Scholar
  35. [35]
    Yamada K M, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell, 2007, 130: 601–610.PubMedCrossRefGoogle Scholar
  36. [36]
    Hebner C, Weaver V M, Debnath J. Modeling morphogenesis and oncogenesis in three-dimensional breast epithelial cultures. Annual Rev Pathol, 2008, 3: 313–339.CrossRefGoogle Scholar
  37. [37]
    Pure E. The road to integrative cancer therapies: emergence of a tumor-associated fibroblast protease as a potential therapeutic target in cancer. Expert Opin Ther Targets, 2009, 13: 967–973.PubMedCrossRefGoogle Scholar
  38. [38]
    Grothey A, Ellis L M. Targeting angiogenesis given by vascular endothelial growth factors using antibody-base therapies. Cancer J, 2008, 14: 170–177.PubMedCrossRefGoogle Scholar
  39. [39]
    Warburg O. On respiratory impairment in cancer cells. Science, 1956, 124: 269–270.PubMedGoogle Scholar
  40. [40]
    Lindner D, Raghavan D. Intra-tumoural extra-cellular pH: a useful parameter of response to chemotherapy in syngeneic tumor lines. Br J Cancer, 2009, 100: 1287–1291.PubMedCrossRefGoogle Scholar
  41. [41]
    Morita T, Nagaki T, Fukuda I, et al. Clastogenicity of low pH to various cultured mammalian cells. Mutat Res, 1992, 268: 297–305.PubMedCrossRefGoogle Scholar
  42. [42]
    Luciani F, Spada M, De Milito A, et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst, 2004, 96: 1702–1713.PubMedCrossRefGoogle Scholar
  43. [43]
    You H, Jin J, Shu H, et al. Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett, 2009, 280: 110–119.PubMedCrossRefGoogle Scholar
  44. [44]
    Gatenby R A, Gawlinski E T, Gmitro A F, et al. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res, 2006, 66: 5216–5223.PubMedCrossRefGoogle Scholar
  45. [45]
    Gatenby, Gillies. Why do cancers have high aerobic glycolysis? Nat Rev Cancer, 2004, 4: 891–899.PubMedCrossRefGoogle Scholar
  46. [46]
    Martinez-Zaguilan R, Seftor E A, Seftor R E, et al. Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis, 1996, 14: 176–186.PubMedCrossRefGoogle Scholar
  47. [47]
    Rofstad E K, Mathiesen B, Kindem K, et al. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res, 2006, 66: 6699–6707.PubMedCrossRefGoogle Scholar
  48. [48]
    Gupta G P, Massague J. Cancer metastasis: building a framework. Cell, 2006, 127: 679–695.PubMedCrossRefGoogle Scholar
  49. [49]
    Coussens L M, Fingleton B, Matrisian L M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science, 2002, 295: 2387–2392.PubMedCrossRefGoogle Scholar
  50. [50]
    Lu X, Qin W, Li J, et al. The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res, 2005, 65: 6843–6849.PubMedCrossRefGoogle Scholar
  51. [51]
    Nishi T, Forgac M. The vacuolar (H+)-ATPases—nature’s most versatile proton pumps. Nat Rev Mol Cell Biol, 2002, 3: 94–103.PubMedCrossRefGoogle Scholar
  52. [52]
    Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 1994, 367: 645–648.PubMedCrossRefGoogle Scholar
  53. [53]
    Reya T, Morrison S J, Clarke M F, et al. Stem cells, cancer, and cancer stem cells. Nature, 2001, 414: 105–111.PubMedCrossRefGoogle Scholar
  54. [54]
    Singh S K, Hawkins C, Clarke I D, et al. Identification of human brain tumor initiating cells. Nature, 2004, 432: 396–401.PubMedCrossRefGoogle Scholar
  55. [55]
    Bao S, Wu Q, McLendon R E, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 2006, 444: 756–760.PubMedCrossRefGoogle Scholar
  56. [56]
    Al-Hajj M, Wicha M S, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 2003, 100: 3983–3988.PubMedCrossRefGoogle Scholar
  57. [57]
    Ginestier C, Hur M H, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 2007, 1: 555–567.PubMedCrossRefGoogle Scholar
  58. [58]
    O’Brien C A, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature, 2007, 445: 106–110.PubMedCrossRefGoogle Scholar
  59. [59]
    Ricci-Vitiani L, Lombardi D G, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature, 2007, 445: 111–115.PubMedCrossRefGoogle Scholar
  60. [60]
    Li C, Heidt D G, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res, 2007, 67: 1030–1037.PubMedCrossRefGoogle Scholar
  61. [61]
    Hermann P C, Huber S L, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 2007, 1: 313–323.PubMedCrossRefGoogle Scholar
  62. [62]
    Yin S, Li J, Hu C, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer, 2007, 120: 1444–1450.PubMedCrossRefGoogle Scholar
  63. [63]
    Ma S, Chan K W, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 2007, 132: 2542–2556.PubMedCrossRefGoogle Scholar
  64. [64]
    Yang Z F, Ho D W, Ng M N, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 2008, 13: 153–166.PubMedCrossRefGoogle Scholar
  65. [65]
    Kelly P N, Dakic A, Adams J M, et al. Tumor growth need not be driven by rare cancer stem cells. Science, 2007, 317: 337.PubMedCrossRefGoogle Scholar
  66. [66]
    Quintana E, Shackleton M, Sabel M S, et al. Efficient tumor formation by single human melanoma cells. Nature, 2008, 456: 593–598.PubMedCrossRefGoogle Scholar
  67. [67]
    Shultz L D, Lyons B L, Burzenski L M, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol, 2005, 174: 6477–6489.PubMedGoogle Scholar
  68. [68]
    Visvader J E, Lindeman G J. Cancer stem cells in solid tumors: accumulating evidence and unresolved questions. Nat Rev Cancer, 2008, 8: 755–768.PubMedCrossRefGoogle Scholar
  69. [69]
    Yin S, Li J, Hu C, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer, 2007, 120: 1444–1450.PubMedCrossRefGoogle Scholar
  70. [70]
    Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology, 2009, 136: 1012–1024.PubMedCrossRefGoogle Scholar
  71. [71]
    Yang W, Yan H X, Chen L, et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res, 2008, 68: 4287–4295.PubMedCrossRefGoogle Scholar
  72. [72]
    Yang Z F, Ho D W, Ng M N, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 2008, 13: 153–166.PubMedCrossRefGoogle Scholar
  73. [73]
    Nowell P C. The clonal evolution of tumor cell populations. Science, 1976, 194: 23–28.PubMedCrossRefGoogle Scholar
  74. [74]
    Shackleton M, Quintana E, Fearon E R, et al. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell, 2009, 138: 822–829.PubMedCrossRefGoogle Scholar
  75. [75]
    Zhao Y, Wang X, Wang T, et al. Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization. Hepatology, 2011, 53: 493–503.PubMedCrossRefGoogle Scholar

Copyright information

© Zhejiang University Press, Hangzhou and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Jianren Gu
    • 1
  • Wenxin Qin
    • 1
  • Zhigang Zhang
    • 1
  1. 1.State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

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