Wybrane czynniki prognostyczne w raku jajnika

• Authors: Janina Markowska , Wiesława Bednarek , Anna Markowska

Title variants

EN

Selected prognostic factors in ovarian cancer

• Languages of publication: EN PL

Abstracts

EN

The authors discuss several predictive factors related to ovarian cancer, both those associated with prognosis and those potentially useful in targeted therapy thereof. Expression of mRNA BRCA1, VEGF and its receptors, CXCR4, HER-2, HIF-1α, COX-2, NM-23, KAI 1, IGF-1R, kisspeptin, neuropilin and Prox-1 gene are discussed. Expression of mRNA BRCA1 is associated not only with hereditary ovarian cancer, but also with its sporadic form. Higher expression correlates with a better response to taxanes. Hopefully, mRNA BRCA1 level in women with sporadic ovarian cancer will become a useful parameter, qualifying patients for a particular chemotherapy protocol. BRMS1 acts as a gene inhibiting development of metastases in ovarian cancer. Levels of mRNA for BRMS1 are lower in late than in early stage ovarian cancer. The VEFG family is involved in angio- and lymphangiogenesis and includes 5 glycoproteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E), which acting upon receptors VEGFR1-3. Neuropilin 1 plays a role in angiogenesis, while neuropilin 2 modulates lymphangiogenesis, similar to the Prox-1 gene. COX-2 mediates the release of pro-angiogenic factors. HIF-1α expression is associated with resistance of hypoxic cancer cells against cytostatics and radiation. Expression of c-Met correlates with poorly differentiated cancer types. The SDF-1/CXCR4 complex plays a key role in the development of cancer metastases. Survivin is present in cancer cells only, where it inhibits apoptosis and promotes the development of cancer. Metastases suppressor gene (BRMS1) and receptors for VEGF, CXCR4, HER-2, HIF-1α and COX-2, may serve as targets for targeted therapy. At present, an increasing number of studies focus on VEGF receptors. Poor expression of NM-23 and KAI 1 correlate with tumor ability to form metastases. The authors discuss the role of biological markers for clear-cell ovarian cancer (IGF-1R and kisspeptin). Promising topics for future studies are survivin, neuropilin and the Prox-1 gene.

PL

W artykule omówiono szereg czynników prognostycznych związanych nie tylko z rokowaniem, ale również z możliwością zastosowania terapii tarczowej w raku jajnika. Przedstawiono ekspresję mRNA BRCA1, VEGF i jego receptorów, CXCR4, HER-2, HIF-1α, COX-2, NM-23, KAI 1, IGF-1R, kisspeptyny, neuropiliny i genu Prox-1. Ekspresja mRNA BRCA1 wiąże się nie tylko z dziedzicznym rakiem jajnika, ale również z rakiem sporadycznym. Wyższa ekspresja powoduje lepszą odpowiedź na taksany. Przypuszcza się, że zawartość mRNA BRCA1 u kobiet z rakiem sporadycznym może służyć do selekcji pacjentek do odpowiedniego typu chemioterapii. BRMS1 działa jako gen hamowania przerzutów w raku jajnika. Poziomy mRNA dla BRMS1 są niższe w zaawansowanych stadiach raka niż we wczesnych. Rodzina VEGF związana z angiogenezą i limfangiogenezą składająca się z 5 glikoprotein (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E) działa poprzez receptory VEGFR1-3. Neuropilina 1 odgrywa rolę w angiogenezie, a typ drugi moduluje proces limfangiogenezy, podobnie jak gen Prox-1. W uwalnianiu czynników proangiogennych bierze udział COX-2. Ekspresja HIF-1α związana jest z opornością niedotlenionych komórek raka na leczenie chemiczne i napromienianiem. Ekspresja c-Met wiąże się z niższym zróżnicowaniem raka. Kompleks SDF-1/CXCR4 odgrywa kluczową rolę w tworzeniu przerzutów komórek nowotworowych. Surwiwina występująca wyłącznie na komórkach nowotworowych poprzez hamowanie apoptozy promuje rozwój raka. Gen supresji przerzutów (BRMS1), podobnie jak receptory VEGF, CXCR4, HER-2, HIF-1α, COX-2, może być tarczą dla terapii celowanej. Obecnie coraz więcej badań dotyczy inhibitorów VEGF. Obniżona ekspresja NM-23 oraz KAI 1 koreluje ze zdolnością do przerzutowania. Omówiono markery biologiczne dla raka jasnokomórkowego jajnika (IGF-1R i kisspeptynę). Ciekawym obiektem badań może być surwiwina, neuropilina i gen Prox-1.

Keywords

EN

BRCA1; HIF-1α; VEGF; mRNA; mRNA BRCA1; markery prognostyczne w raku jajnika; prognostic factors in ovarian cancer; targeted therapy; terapia celowana

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Current Gynecologic Oncology
• Year: 2010
• Volume: 8
• Issue: 1
• Pages: 8-20

Contributors

author

Janina Markowska

• Katedra i Klinika Onkologii Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu.

author

Wiesława Bednarek

• I Katedra i Klinika Ginekologii Onkologicznej i Ginekologii UM w Lublinie

author

Anna Markowska

• Klinika Perinatologii i Chorób Kobiecych UM im. K. Marcinkowskiego w Poznaniu, ul. Polna 33, 60-535 Poznań.

References

• 1. Zografos G.C., Panou M., Panou N.: Common risk factors of breast and ovarian cancer: recent view. Int. J. Gynecol. Cancer 2004; 14: 721-740.
• 2. Frank T.S., Deffenbaugh A.M., Reid J.E. i wsp.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J. Clin. Oncol. 2002; 20: 1480-1490.
• 3. Gronwald J., Huzarski T., Byrski B. i wsp.: Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status. J. Med. Genet. 2006: 43: 424-428.
• 4. Rubin S.C., Benjamin I., Behbakht K. i wsp.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N. Engl. J. Med. 1996; 335: 1413-1416.
• 5. Boyd J., Sonoda Y., Federici M.G. i wsp.: Clinicopatholog-ic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000; 283: 2260-2265.
• 6. Ben David Y., Chetrit A., Hirsh-Yechezkel G. i wsp.: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J. Clin. Oncol. 2002; 20: 463-466.
• 7. Chetrit A., Hirsh-Yechezkel G., Ben David Y., i wsp.: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the National Israeli Study of Ovarian Cancer. J. Clin. Oncol. 2008; 26: 20-25.
• 8. Cannistra S.A.: BRCA-1 in sporadic epithelial ovarian cancer: lessons learned from the genetics of hereditary disease. Clin. Cancer Res. 2007; 13: 7225-7227.
• 9. Lafarge S., Sylvain V, Ferrara M., Bignon Y.J.: Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 2001; 20: 6597-6606.
• 10. Buller R.E., Shahin M.S., Geisler J.P., i wsp.: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin. Cancer Res. 2002; 8: 1196-1202.
• 11. Quinn J.E., Kennedy R.D., Mullan P.B. i wsp.: BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 2003: 63: 6221-6228.
• 12. James C.R., Quinn J.E., Mullan P.B. i wsp.: BRCA1 as a predictive marker of survival in sporadic ovarian cancer (Meeting Abstracts). J. Clin. Oncol. 2007; 25: 5512.
• 13. Xu X., Weaver Z., Linke S.P. i wsp.: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 1999; 3: 389-395.
• 14. Kauff N.D.: Is it time to stratify for BRCA mutation status in therapeutic trials in ovarian cancer? J. Clin. Oncol. 2008; 26: 9-10.
• 15. Seraj M.J., Samant R.S., Verderame M.F., Welch D. R.: Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 2000; 60: 2764-2769.
• 16. Zhang S., Lin Q.D., Di W: Suppression of human carcinoma metastasis by the metastasis-suppressor gene, BRMS1. Int. J. Gynecol. Cancer 2006: 16: 522-531.
• 17. Foulkes WD., Campbell I.G., Stamp G.W., Trowsdale J.: Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer. Br. J. Cancer 1993: 67: 268-273.
• 18. Goh P.P., Sze D.M., Roufogalis B.D.: Molecular and cellular regulators of cancer angiogenesis. Curr. Cancer Drug Targets 2007; 7: 743-758.
• 19. Karkkainen M.J., Petrova T.V: Vascular endothelial growth factor receptors in the regulation of angiogenesis and lym-phangiogenesis. Oncogene 2000; 9: 5598-5605.
• 20. Takahashi T., Kalka C., Masuda H. i wsp.: Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 1999; 5: 434-438.
• 21. Jain R.K.: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307: 58-62.
• 22. Achen M.G., Stacker S.A.: Tumor lymphangiogenesis and metastatic spread-new players begin to emerge. Int. J. Cancer 2006; 119: 1755-1760.
• 23. Lin J., Lalani A.S., Harding T.C. i wsp.: Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 2005; 65: 6901-6909.
• 24. He Y., Rajantie I., Pajusola K i wsp.: Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 2005; 65: 4739-4746.
• 25. Shweiki D., Itin A., Soffer D., Keshet E.: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359: 843-845.
• 26. Ferrara N., Gerber H.P., LeCouter J.: The biology of VEGF and its receptors. Nat. Med. 2003; 9: 669-676.
• 27. Shimogai R., Kigawa J., Itamochi H. i wsp.: Expression of hypoxia-inducible factor 1a gene affects the outcome in patients with ovarian cancer. Int. J. Gynecol. Cancer 2008; 18: 499-505.
• 28. Shen G.H., Ghazizadeh M., Kawanami O. i wsp.: Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Br. J. Cancer 2000; 83: 196-203.
• 29. Sönmezer M., Güngör M., Ensari A., Ortaç F.: Prognostic singnificance of tumor angiogenesis in epithelial ovarian cancer: in association with transforming growth factor P and vascular endothelial growth factor. Int. J. Gynecol. Cancer 2004; 14: 82-88.
• 30. Narazaki M., Segarra M., Tosato G.: Neuropilin-2: a new molecular target for antiangiogenic and antitumor strategies. J. Natl. Cancer Inst. 2008; 100: 81-83.
• 31. Gu C., Rodriguez E.R., Reimert D.V i wsp.: Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 2003; 5: 45-57.
• 32. Favier B., Alam A., Barron P. i wsp.: Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 2006; 108: 1243-1250.
• 33. Caunt M., Mak J., Liang WC. i wsp.: Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 2008; 13: 331-342.
• 34. Baba T., Kariya M., Higuchi T. i wsp.: Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol. Oncol. 2007; 105: 703-711.
• 35. Zinovieva R.D., Duncan M.K., Johnson T.R. i wsp.: Structure and chromosomal localization of the human homeobox gene Prox1. Genomics 1996; 35: 517-522.
• 36. Wigle J.T., Oliver G.: Prox1 function is required for the development of the murine lymphatic system. Cell 1999; 98: 769-778.
• 37. Hirakava S., Hong Y.K., Harvey N. i wsp.: Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am. J. Pathol. 2003; 162: 575-586.
• 38. Hong Y.K., Harvey N., Noh Y.H. i wsp.: Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev. Dyn. 2002; 225: 351-357.
• 39. Wilting J., Papoutsi M., Christ B. i wsp.: The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB J. 2002; 16: 1271-1273.
• 40. Vordermark D., Brown J.M.: Endogenous markers of tumor hypoxia predictors of clinical radiation resistance? Strahlen-ther. Onkol. 2003; 179: 801-811.
• 41. Zhou J., Schmid T., Schnitzer S., Brune B.: Tumor hypoxia and cancer progression. Cancer Lett. 2006; 237: 10-21.
• 42. Shimogai R., Kigawa J., Itamochi H. i wsp.: Expression of hypoxia-inducible factor 1a gene affects the outcome in patients with ovarian cancer. Int. J. Gynecol. Cancer 2008; 18; 499-505.
• 43. Semenza G.L.: HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol. 2000; 88: 1474-1480.
• 44. Yo Y., Morishita R., Nakamura S. i wsp.: Potential role of hepatocyte growth factor in the maintenance of renal structure: anti-apoptotic action of HGF on epithelial cells. Kidney Int. 1998; 54: 1128-1138.
• 45. Medico E., Mongiovi A.M., Huff J. i wsp.: The tyrosine kinase receptors Ron and Sea control “scattering” and morphogenesis of liver progenitor cells in vitro. Mol. Biol. Cell 1996; 7: 495-504.
• 46. Ayhan A, Ertunc D, Tok EC, Ayhan A. Expression of the c-Met in advanced epithelial ovarian cancer and its prognostic significance. Int. J. Gynecol. Cancer 2005; 15: 618-623.
• 47. Schlessinger J.: Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211-225.
• 48. Steffensen K.D., Waldstr0m M., Jeppesen U. i wsp.: The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer. Int. J. Gynecol. Cancer 2007; 17: 798-807.
• 49. Bookman M.A., Darcy K.M., Clarke-Pearson D. I wsp.: Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J. Clin. Oncol. 2003; 21: 283-290.
• 50. Kupryjańczyk J., Mądry R., Plisiecka-Hałasa J. i wsp.: P53 status determines clinical significance of ERBB2 expression in ovarian cancer. Br. J. Cancer 2004; 91: 1916-1923.
• 51. Toomey D.P, Murphy J.F., Conlon C.: COX-2, VEGF and tumour angiogenesis. Surgeon 2009; 3: 174-180.
• 52. Wróbel T., Mazur G., Surowiak P. i wsp.: Increased expression of vascular endothelial growth factor in bone marrow of multiple myeloma patients. Eur. J. Intern. Med. 2003; 14: 98-100.
• 53. Li W, Ji Z.L., Zhuo G.C. i wsp.: Effects of a selective cyclo-oxygenase-1 inhibitor in SKOV-3 ovarian carcinoma xenograft-bearing mice. Med. Oncol. 2009; 26: 170-177.
• 54. Seo S.S., Song Y.S., Kang D.H. i wsp. Expression of cyclo-oxygenase-2 in association with clinicopatological prognostic factors and molecular markers in epithelial ovarian cancer. Gynecol. Oncol. 2004; 92: 927-933.
• 55. Gasparini G, Longo R, Sarmieto R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol. 2003; 10: 605-615.
• 56. Patel VA., Dunn M.J., Sorokin A.: Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. J. Biol. Chem. 2002; 277: 38915-38920.
• 57. Kuohung W, Kaiser U.B.: GPR54 and KiSS-1: role in regulation of puberty and reproduction. Rev. Endocr. Metab. Disord. 2006; 7: 257-263.
• 58. Harms J.F., Welch D.R., Miele M.E.: KISS1 metastasis suppression and emergent pathways. Clin. Exp. Metastatic 2003; 20: 11-18.
• 59. Becker J.A., Mirjolet J.F., Bernard J. i wsp.: Activaction of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other Gq-coupled receptors. Biol. Biophys. Res. Commun. 2005; 326: 677-686.
• 60. Prentice L.M., Klausen C., Kalloger S. i wsp.: Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear subtype ovarian carcinoma. BMC Med. 2007; 5: 33.
• 61. Liu FS., Dong J.T, Chen J.T i wsp.: KAI1 metastasis suppressor protein is down-regulated during the progression of human endometrial cancer. Clin. Cancer Res. 2003; 9: 1393-1398.
• 62. Schindl M., Birner P., Breitenecker G., Oberhuber G.: Downregulation of KAI1 metastasis suppressor protein is associated with a dismal prognosis in epithelial ovarian cancer. Gynecol. Oncol. 2001; 83: 244-248.
• 63. Mandai M., Konishi I., Koshiyama M. i wsp.: Expression of metastasis-related nm23-H1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. Cancer Res. 1994; 54: 1825-1830.
• 64. Galani E., Sgouros J., Petropoulu C. i wsp.: Correlation of MDR-1, nm23-H1 and HSema E gene expression with histo-pathological findings and clinical outcome in ovarian and breast cancer patients. Anticancer Res. 2002; 22: 2275-2280.
• 65. Scambia G., Ferrandina G., Marone M. i wsp.: nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters. J. Clin. Oncol. 1996; 14: 334-342.
• 66. Tas F., Tuzlali S., Aydiner A. i wsp.: Prognostic role of nm23 gene expression in patients with ovarian cancer. Am. J. Clin. Oncol. 2002; 25: 164-167.
• 67. Mülle A., Homey B., Soto H. i wsp.: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-56.
• 68. Kucia M., Jankowski K., Reca R. i wsp.: CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J. Mol. His-tol. 2004; 35: 233-245.
• 69. Hall J.M., Korach K.S. Stromal cell-derived factor 1a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol. Endocrinol. 2003; 17: 792-797.
• 70. Hunter A.M., LaCasse E.C., Korneluk R.G.: The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 2007; 12: 1543-1568.
• 71. Ambrosini G., Adida C., Altieri D.C.: A novel anti-apopto-sis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 1997; 8: 917-921.
• 72. Tamm I., Wang Y., Sausville E. i wsp.: IAP-family protein apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998; 58: 5315-5320.
• 73. Liguang Z., Peishu L., Hongluan M. i wsp.: Survivin expression in ovarian cancer. Exp. Oncol. 2007; 29: 121-125.
• 74. Talbot D.C., Davies J., Callies S. i wsp.: First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. J. Clin. Oncol. 2008; 26 (suppl.), abstr. 3518.
• 75. Ferrandina G., Legge F., Martinelli E. i wsp.: Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters. Br. J. Cancer 2005; 92: 271-277.
• 76. Pollak M.N., Schernhammer E.S., Hankinson S.E.: Insulinlike growth factors and neoplasia. Nat. Rev. Cancer 2004; 4: 505-518.
• 77. Wang Y., Sun Y.: Insulin-like growth factors receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis. Curr. Cancer Drug Targets 2002; 2: 191-207.
• 78. Kobel M., Xu H., Bourne P.A. i wsp.: IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod. Pathol. 2009; 22: 469-475.

• Document Type: article