Translational science

  • Krishnansu Tewari
  • Bradley Monk


Approximately 150 years ago, the concept of cancer ‘stem cell’ populations was introduced [1]. As certain subpopulations of cancer cells have inherited normal stem cell properties including capacity for self-renewal, ability to differentiate, activate anti-apoptotic pathways, and metastasize, cancer stem cell response correlates directly with survival [2–4]. Taken further, the relative amount of chemotherapy-induced neutropenia (i.e., differentiated cell response) would be expected to correlate with survival (i.e., cancer stem cell response). It has been postulated that with increasing severity of neutropenia, a greater fractional kill of cancer stem cells occurs, potentially improving survival. Further work is required to determine whether the severity (rather than just the occurrence) of neutropenia correlates with clinical outcome.


Vascular Endothelial Growth Factor Ovarian Cancer Cancer Stem Cell National Comprehensive Cancer Network Serous Carcinoma 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Durante F. Nesso fisio-pathologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni. Arch Memor Observ Chir Pract. 1874;11:217-226.Google Scholar
  2. 2.
    Wicha MS, Liu S, Dontu G. Cancer stem cells: An old idea — a paradigm shift. Cancer Res. 2006;66:1883-1890.Google Scholar
  3. 3.
    Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355:1253-1261.Google Scholar
  4. 4.
    Brenton JD, Stingl J. Stem cells: anatomy of an ovarian cancer. Nature. 2013;495:183-184.Google Scholar
  5. 5.
    Curley MD, Garrett LA, Schorge JO, Foster R, Rueda BR. Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer. Front Biosci. 2011;16:368-392.Google Scholar
  6. 6.
    Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature. 1979;278:261-263.Google Scholar
  7. 7.
    Reles A, Wen WH, Schmider A, et al. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res. 2001;7:2984‑2997.Google Scholar
  8. 8.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21-33.Google Scholar
  9. 9.
    Jacobs IJ, Kohler MF, Wiseman RW, et al. Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation. J Natl Cancer Inst. 1992;84:1793-1798.Google Scholar
  10. 10.
    Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 2008;68:3077-3080.Google Scholar
  11. 11.
    Prathapam T, Aleshin A, Guan Y, Gray JW, Martin GS. p27Kip1 mediates addiction of ovarian cancer cells to MYCC (c-MYC) and their dependence on MYC paralogs. J Biol Chem. 2010;285:32529-32538.Google Scholar
  12. 12.
    Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250:1684-1689.Google Scholar
  13. 13.
    Bowcock AM, Anderson LA, Friedman LS, et al. THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. Am J Hum Genet. 1993;52:718-722.Google Scholar
  14. 14.
    Simard J, Feunteun J, Lenoir G, et al. Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. Hum Mol Genet. 1993;2:1193-1199.Google Scholar
  15. 15.
    Tonin P, Serova O, Simard J, et al. The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21. Hum Mol Genet. 1994;3:1679-1682.Google Scholar
  16. 16.
    Smith SA, DiCioccio RA, Struewing JP, et al. Localisation of the breast-ovarian cancer susceptibility gene (BRCA1) on 17q12-21 to an interval of < or = 1 cM. Genes Chromosomes Cancer. 1994;10:71-76.Google Scholar
  17. 17.
    Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265:2088-2090.Google Scholar
  18. 18.
    Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in common pathway of genome protection. Nat Rev Cancer. 2012;12:68-78.Google Scholar
  19. 19.
    Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007;2111:26-35.Google Scholar
  20. 20.
    Pool M. Mini case report: early serous carcinoma in fallopian tube in BRCA2 carrier. Last accessed November 17, 2014.Google Scholar
  21. 21.
    Norquist BM, Garcia RL, Allison KH, et al. The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations. Cancer. 2010;116:5261-5271.Google Scholar
  22. 22.
    Lonning PE, Bjornslett M, Knappskog S, et al. Effect of WBC BRCA1 promote methylation on ovarian cancer risk. J Clin Oncol. 2011;29(suppl):5029.Google Scholar
  23. 23.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.Google Scholar
  24. 24.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. 82 • The 21st Century Handbook of Clinical Ovarian CancerGoogle Scholar
  25. 25.
    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609-615.Google Scholar
  26. 26.
    Hampton OA, Hollander PD, Miller CA, et al. A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Res. 2009;19:167-177.Google Scholar
  27. 27.
    Tewari KS, Mehta RS, Burger RA, et al. Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma. Gynecol Oncol. 2005;98:360-368.Google Scholar
  28. 28.
    Tewari KS, Kyshtoobayeva AS, Mehta RS, et al. Biomarker conservation in primary and metastatic epithelial ovarian cancer. Gynecol Oncol. 2000;78:130-136.Google Scholar
  29. 29.
    Schrag D, Garewal HS, Burstein HJ, et al. American Society of Clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol. 2004;22:3631-3638.Google Scholar
  30. 30.
    Burstein HJ, Mangu PB, Somerfield MR, et al. American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29:3328-3330.Google Scholar
  31. 31.
    Rutherford T, Orr J Jr, Grendys E Jr, et al. A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol Oncol. 2013;131:362-367.Google Scholar
  32. 32.
    Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439-442.Google Scholar
  33. 33.
    Malpica A, Deavers MR, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28:496-504.Google Scholar
  34. 34.
    Ide AG BN, Warren SL. Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol. l939;42:891-899.Google Scholar
  35. 35.
    Folkman J ME, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. l1971;133:275-288.Google Scholar
  36. 36.
    Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med (Berl). 1999;77:527-543.Google Scholar
  37. 37.
    Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841-844.Google Scholar
  38. 38.
    Borgstrom P, Hillan KJ, Sriramarao P, Ferrara N. Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 1996;56:4032-4039.Google Scholar
  39. 39.
    Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407:242-248.Google Scholar
  40. 40.
    Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des. 2007;13:2025-2044.Google Scholar
  41. 41.
    Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338-340.Google Scholar
  42. 42.
    Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967-974.Google Scholar
  43. 43.
    Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma – mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol. 2014;132:496‐505.Google Scholar
  44. 44.
    Gourley C, Michie CO, Keating KE, et al. Establishing a molecular taxonomy for epithelial ovarian cancer (EOC) from 363 formalin-fixed paraffin embedded (FFPE) specimens. J Clin Oncol. 2011;29:(suppl; abstr 5000).Google Scholar
  45. 45.
    D’Amours D, Desnoyers S, D’Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J. 1999;342:249-268.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Krishnansu Tewari
    • 1
  • Bradley Monk
    • 2
  1. 1.University of California, Irvine Medical Gynecologic Oncology GroupOrangeUSA
  2. 2.St Joseph’s Hospital and Medical Center Division of Gynecologic OncologyPhoenixUSA

Personalised recommendations