Ovarian Cancer: Medical Review Thesis

Despite advancements in the treatment, ovarian cancer-related mortality has been relatively constant for over 30 years. With currently available therapy which includes cytoreductive or debulking surgery followed by platinum-drug-based chemotherapy, ovarian cancer detected at stage I has a survival rate of 94%. Cytoreductive surgery is an “optimal” surgery that leaves not larger than 2 cm tumor inside the body as a suggestive measure to minimize the surgery-related complications with patient’s conditions. Platinum containing chemotherapeutic drugs like taxane help eradicate the residual portion of the tumor. Detection of ovarian cancer at later (metastasis) stages (III and IV) reduces the survival chance to 35% even though patients are well treated. This is because of relapse of the disease in 15% of the patients which is mostly incurable. Ovarian cancer often gives non-specific symptoms, which makes it difficult to screen at an early stage of the disease. Strategies to evaluate biomarkers that help in diagnosing cancer at stage I or II and also in the prognosis of the relapse of the disease in the post-hospitalized patients would enable a better survival chance of the patients. The most popular diagnostic mechanism is transvaginal or pelvic ultrasound followed by serum detection of cancer antigen 125 (CA125) also known as Mucin 16 (MUC16), which is a high molecular weight cell surface-associated glycoprotein (Scholler et al. 2006). Unfortunately, only 35% of patients can be screened for stage I cancer using the combined methods. CA125 is a reliable marker for monitoring the response of treatment and disease recurrence, rather than for early diagnosis.

During the past decade numerous biomarkers, independently or in conjunction with CA125, were clinically evaluated for their cancer-associated over-expression, and their expression in normal and cancerous OSE cell lines was verified using immunohistochemical procedures. Claudin-3 and -4 are the tight junction epithelial surface protein associated with increased invasiveness and metalloproteinase-II activity in OEC, and they served as suitable markers alternate to CA125 to monitor recurrence of the disease in patients non-responsive to chemotherapy (Litkouhi et al. 2007). B7-H4, an immunomodulatory protein, is another CA125 independent biomarker highly expressed in ovarian cancer tissues compared to the normal tissues (Simon et al. 2007). Serum cytokines, notably epidermal growth factor (EGF), monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF) tumor necrosis factor-α (TNF- α), and interleukin-6 and -8 are the batches of inflammatory markers that respond to stage I of OEC and enhance the CA125 diagnostic sensitivity (Lambeck et al. 2007). These inflammatory compounds also up-regulate the anti-inflammatory c-reactive proteins (CRP), and in situations of metastasis, this marker is correlated with the spread of cancer to other tissues (Hefler et al. 2008). Another batch of about 24 cancer-associated proteins was evaluated successfully as blood markers of OEC. These included WAP four-disulfide core domain 2 (WFDC2), Mesothelin (MSLN), insulin-like growth factor-2 (IGF-2), Chitinase 3-like 1 (cartilage glycoprotein-39) (CHI3L1) etc. In combination with CA125, these markers remarkably increased the stage I diagnostic ability of OEC (Palmer et al. 2008). Visintin et al. (2008) however considered the hypothalamic-pituitary-ovarian axis, rather than exclusively ovary, as a source of marker proteins and evaluated ovarian IGF-II and prolactin, and hypothalamic leptin in combination with CA125 as diagnostic biomarker set with superior efficiency compared to CA125 alone. Among the other proven cancer-specific biomarkers are the serine proteases, Kallikreins (KLK6,7,10,11,14) (Paliouras, Borgono & Diamandis, 2007), prostaglandin synthesizing cyclooxygenase-1 (COX-1) (Daikoku et al. 2005), and inducible nitric oxide synthase (iNOS) (Anttila et al. 2007). Some of these diagnostic proteins once overexpress also selectively kill cancerous cells, and therefore they are of therapeutic importance too. There are also prognostic markers that determine the nonrecurrent disease-free survival of the patients, and two such biomarkers are P53 and P21 proteins, whose overexpression relates to, apart from cell cycle arrest and apoptosis induction, downregulation of several oncogenes and immunomodulatory, pro-inflammatory, and angiogenic genes directly associated with cancer progression (Goodheart et al. 2005; Chu, Hengst & Slingerland 2008).

Most of the aforementioned biomarkers are normal cell proteins whose serum concentration can be affected by the hormonal regime that changes during pregnancy and in anestrous and estrous cycles. Hence, the efficacy of the biomarkers in cancer detection depends on the physiological alterations of such proteins prevailing in the OSE layer, in follicular fluid, and serum depending on the procaine and endocrine conditions regulating the expression of such proteins. For this kind of basic investigation, suitable animal models and cell cultures are quite suitable, as for ethical reasons it may be difficult to employ human subjects. In this study, we have applied several proliferative markers and applied different in vivo and in vitro conditions to monitor their expression at gene and protein levels. The same line of investigation can be extended by using the above cancer-determinant biomarkers. If pregnancy and oral contraceptive drugs including the progesterone-based pill suppress tumor formation, one can judge this fact by using animal ovarian OSE cells and the cells grown in cell cultures, just by replacing the existing markers with the chunk of human cancer biomarkers. In this way, one can shortlist a few valid markers that are minimally affected by the paracrine or endocrine factors, while they only respond to the conditions that lead to tumorigenesis. Among the described human biomarkers we have applied the P53 marker in the animal model and cultured cells, and our study revealed that progesterone up-regulated the P53 protein synthesis and apoptotic destruction of those mitogenic cells that tend to undergo neoplastic growth. The same attribute in OEC patients may suppress the recurrence of the disease. Thus animal model helps to understand the possible hormonal therapeutic mechanism and to monitor the response of the drug-using P53 biomarker. In nutshell, all these basic investigations in animal models and cell cultures need to be applied to clinical science so that better survival chances and quality lifespan can be attained by way of early cancer diagnosis and efficient recurrence prognosis.

References

1. Anttila, M.A., Voutilainen, K., Merivalo, S., Saarikoski, S. & Kosma, V-M.(2007). Prognostic significance of iNOS in epithelial ovarian cancer. Gynecologic Oncology, 105, 97–103.
2. Chu, I.M., Hengst, L. & Slingerland, J.M.(2008). The Cdk inhibitor p27 inhuman cancer: prognostic potential and relevance to anticancer therapy. Nature Reviews, 8, 253-267.
3. Daikoku, T., Wang, D., Tranguch, S., Morrow, J.D., Orsulic, S., DuBois, R.N. & Dey, S.K.(2005). Cyclooxygenase-1 Is a Potential Target for Prevention and Treatment of Ovarian Epithelial Cancer. Cancer Research, 65(9), 3735-3744.
4. Goodheart, M.J., Ritchie, J., Rose, S.L., Fruehauf, J.P., DeYoung, B.R. & Buller, R.E.(2005). The Relationship of Molecular Markers of p53 Function and Angiogenesis to Prognosis of Stage I Epithelial Ovarian Cancer. Clinical Cancer Research, 11(10), 3733-3742.
5. Hefler, L.A., Concin, N., Hofstetter, G., Marth, C., Mustea, A., Sehouli, J., Zeillinger, R., Leipold, H., Lass, H., Grimm, C., Tempfer, C.B. & Reinthaller, A.(2008). Serum C-Reactive Protein as Independent Prognostic Variable in Patients with Ovarian Cancer. Clinical Cancer Research, 14(3), 710-714.
6. Lambeck,A.J.A., Crijns, A.P.G., Leffers, N., Sluiter, W.J., ten Hoor, K.A., Braid, M., van der Zee, A.G.J., Daemen, T., Nijman, H.W. & Kast, W.M.(2007). Serum Cytokine Profiling as a Diagnostic and Prognostic Tool in Ovarian Cancer: A Potential Role for Interleukin 7. Clinical Cancer Research, 13(8), 2385-2391.
7. Litkouhi, B., Kwong, J., Loz, C-M., Smedley, J.G., McClane, B.A., Aponte, M., Gao, Z., Sarno, J.L., Hinners, J., Welchy, W.R., Berkowitz, R.S., Mok, S.C. & Garner, E.I.O.(2007). Claudin-4 Overexpression in Epithelial Ovarian Cancer Is Associated with Hypomethylation and Is a Potential Target for Modulation of Tight Junction Barrier Function Using a C-Terminal Fragment of Clostridium perfringens Enterotoxin. Neoplasia. 9(4), 304 – 314.
8. Paliouras, M., Borgono, C. & Diamandis, E.P.(2007). Human tissue kallikreins: The cancer biomarker family. Cancer Letters, 249, 61–79.
9. Palmer, C., Duan, X., Hawley, S., Scholler, N., Thorpe, J.D., Sahota, R.A., Wong, M.Q., Wray, A., Bergan, L.A., Drescher, C.W., McIntosh, M.W., Brown, P.O., Nelson, B.H. & Urban, N.(2008). Systematic Evaluation of Candidate Blood Markers for Detecting Ovarian Cancer. PLoS ONE, 3(7), e2633, doi:10.1371/journal.pone.0002633.
10. Scholler, N., Crawford, M., Sato, A., Drescher, C.W., O’Briant, K.C., Kiviat, N., Anderson, G.L. & Urban, N.(2006). Bead-Based ELISA for Validation of Ovarian Cancer Early Detection Markers. Clinical Cancer Research, 12(7), 2117-2124.
11. Simon, I., Katsaros, D., de la Longrais, R.I., Massobrio, M., Scorilas, A., Kim, N.W., Sarno, M.J., Wolfert, R.L. & Diamandis, E.P.(2007). B7-H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression. Gynecologic Oncology, 106, 334–341.
12. Visintin, I., Feng, Z., Longton, G., Ward, D.C., Alvero, A.B., Lai, Y., Tenthorey, J., Leiser, A., Flores-Saaib, R., Yu, H., Azori, M., Rutherford, T., Schwartz, P.E. & Mor, G.(2008). Diagnostic Markers for Early Detection of Ovarian Cancer. Clinical Cancer Research, 14(4), 1065-1072.