Folate Receptor: a Potential Target in Ovarian Cancer
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Pteridines 2015; 26(1): 1–12 Review Marie Bartouskova, Bohuslav Melichar and Beatrice Mohelnikova-Duchonova* Folate receptor: a potential target in ovarian cancer Abstract: Ovarian cancer is the most frequent cause of Introduction gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a Folic acid antagonists have been used in the treatment poor prognosis. The standard treatment for advanced dis- of cancer for more than six decades, since 1948 [1]. Folic ease involves maximal cytoreductive surgery and chemo- acid is a vitamin required for cell metabolism, DNA syn- therapy based on platinum compounds and taxanes. thesis, and repair [2]. Two cellular folate uptake pathways Patients presenting at an advanced stage have a higher have been characterized. The first is mediated by trans- risk of recurrence. The development of drug resistance membrane-reduced folate carriers, which represent the currently represents a major obstacle in the systematic predominant pathway for folate uptake by normal human treatment and, therefore, the discovery of new anticancer cells. Whereas in epithelial cancer cells, membrane pro- agents and approaches should improve the poor progno- teins called folate receptors are often highly expressed and sis of these patients. Folate receptor α is overexpressed in mediate the folate uptake by tumors. Epithelial ovarian epithelial ovarian cancer (EOC), but has limited expres- carcinoma (EOC) has the highest expression of these pro- sion in nonmalignant human tissues. The degree of folate teins, making the folate receptor an attractive candidate receptor expression corresponds with the stage and grade for targeted therapy and targeted drug delivery therapy in of the disease. Because of this, folate receptor α seems several types of cancers, specifically in EOC. to be a potential therapeutic target for the treatment of EOC had an age-standardised rates (ASRs) 13.1 per ovarian cancer. Currently, several approaches have been 100,000 inhabitants (2012) [3], with the highest mortality studied to target this protein in ovarian cancer treatment. rate of all gynecologic tumors. Prognostic factors in EOC This review summarizes current knowledge about the are stage, grade, age, histological subtype, performance potential usage of folate receptors as prognostic and pre- status, volume of ascites, extent of residual disease fol- dictive biomarkers as well as their role in the management lowing debulking surgery, and findings at second-look and targeted therapy of ovarian cancer. laparotomy [4]. Parameters of the host response, e.g., the presence of tumor-infiltrating lymphocytes [5] or the Keywords: biomarkers; folate receptor; ovarian cancer; production of neopterin, a biomarker of immune system targeted therapy. activation [6], have also been identified as independ- ent prognostic factors. More research into the prognostic DOI 10.1515/pterid-2014-0013 factors is clearly needed as prognostic factors can help to Received October 28, 2014; accepted November 25, 2014; previously identify patients with poor prognosis and streamline the published online February 6, 2015 development of new approaches and drugs. Currently, the standard treatment for advanced ovarian carcinoma is surgical tumor debulking followed by plati- num and paclitaxel-based combination chemotherapy. However, despite the potentially high response rate to the initial chemotherapy ranging approximately between 60% *Corresponding author: Beatrice Mohelnikova-Duchonova, and 80%, the majority of patients will ultimately experience Department of Oncology, Palacky University Medical School and recurrence [7], and only about 44% survive 5 years after the Teaching Hospital, Olomouc, IP Pavlova 6, 775 25 Olomouc, Czech diagnosis. The development of drug resistance, either de Republic, E-mail: [email protected] Marie Bartouskova and Bohuslav Melichar: Department of novo or induced resistance, significantly limits the long-term Oncology, Palacky University Medical School and Teaching Hospital, efficacy of systemic chemotherapy [8]. For platinum therapy Olomouc, Czech Republic resistant recurrent EOC topotecan, liposomal doxorubicin, 2 Bartouskova et al.: Folate receptors in ovarian cancer etoposide, gemcitabine, vinorelbine, cyclophosphamide, [20]. Moderate expression has been found in the brain, and/or other drugs may be used [9]. Therapeutic approaches breast, bladder, and pancreatic cancers [20]. In the above- that target the host response to neoplasia have so far been mentioned quantitative radioligand-binding study, more limited to the experimental setting [10, 11]. than 50% of pancreatic cancer samples were positive for Despite the fact that anti-folic acid chemotherapy has FR expression, but the study using immunohistochemistry been used for more than six decades, a new area for the demonstrated only 13% of pancreatic cancer samples as exploration of anti-folate therapy has been opened with positively staining [21]. This discrepancy could be explained the advent of targeted therapy and with the development by the antibody specificity, thin slicing of samples, where of new targeted approaches in medical oncology. More- antigen retrieval is compromised, or by the expression over, folate receptors may be not only the target for of isoforms other than α-isoforms, as in the immunohis- anticancer therapy, but also a potential predictive and tochemical study, anti-FRα antibody has been used. Low prognostic biomarker and a target for tumor imaging. FR expression has been reported in the liver, colorectal, This review summarizes published data concerning prostate, lymphoma, and head and neck carcinomas [20]. the folate receptors, their potential usage as prognostic Despite the fact that among all other human tissue types and predictive biomarker as well as their role in the detec- ovarian malignancies have the highest FR expression, the tion and targeted therapy of EOC, and seeks to define level of expression is highly dependent on tumor histol- future research directions. ogy. Almost 100% of nonmucinous primary and metastatic ovarian tumors were found to have high FR expression, whereas mucinous tumors express very low or nondetect- able FR levels [20]. Moreover, it seems that the metastatic Folate receptor – structure, tumors generally express higher levels of FR compared expression, and function to the primary tumors [20, 21]. FR expression seems to provide a growth advantage to the tumor by greater folate Folate receptors (FRs) are glycosylphosphatidylinositol- uptake resulting in rapid cellular growth and division [14]. anchored membrane proteins of 38–40 kDa that bind folic Consequently, FR protein expression has been found to acid or folate-drug conjugates with high affinity [12]. FRs be associated with tumor progression, dedifferentiation are encoded by a multigene family FOLR (namely, FOLR1, (grade), decreased survival, and platinum resistance [22– FOLR2, and FOLR3), which is localized to chromosome 24]. Toffoli et al. formulated a hypothesis that FRα might 11q13.3–q14.1 [13]. FRs are membrane proteins that play an increase the repair of DNA damage caused by platinum via important role mainly in the cellular accumulation of folates increased folate cellular uptake [23]. Patients with subopti- and antifolates. Folate (pteroyl-l-glutamic acid, vitamin B9) mal debulking surgery had significantly higher tissue FRα is an essential vitamin that is important for DNA replication expression levels in contrast with patients with optimal and cell division. Three types of folate receptors (FRα, FRβ, surgery. More over, a higher expression of FRα was an inde- and FRγ) have been distinguished [14]. Each of folate recep- pendent pro gnostic factor associated with inferior disease- tors has tissue specific distribution and different folate- free survival and overall survival of patients [25]. binding potential [15]. FRα binds folic acid with high affinity There is evidence that FR might be involved in malig- and transports folate by receptor-mediated endocytosis [14]. nant transformation, tumor progression, and treatment FR has been discovered as a tumor marker of EOC cell outcomes. In addition to the modulation of treatment out- line in 1991 [16], and FR expression has been reported in comes of standard platinum-based chemotherapy, FR is 90% of EOC cases. Subsequently, different levels of FR currently studied as a promising potential target for the tar- expression were observed in various human tumors and geted therapy. Moreover, because FR has been confirmed to normal tissues. In contrast to cancer cells, most of the non- be a tumor-associated antigen in ovarian cancer, it may be malignant tissues express low to negligible levels of FR, used for selective targeted delivery of drugs to tumor cells. with the exception of the kidney and the lung. FR is limited to the apical membrane of the proximal tubule cells of human kidney and lung pneumocytes [17, 18]. However, in lung tissue, FR seems not to be able to capture folates Folate receptor as a target for from the circulation as folate-drug conjugates fail to accu- anticancer therapy mulate in the lungs of patients [19]. Besides EOC, a number of other cancers have the high levels of FR, namely, renal The FR represents a potential target for targeted therapy cell carcinomas, lung cancer, and endometrial carcinoma in some human cancers [26]. As the above-mentioned Bartouskova et al.: Folate receptors in ovarian cancer 3 studies have shown a significant association