(CANCER RESEARCH 49, 1505-1508, March 15. 1989] Prostaglandin and Thromboxane Synthesis by Human Intracranial Tumors1

Maria Grazia Castelli, Chiara Chiabrando,2 Roberto Fanelli, Luciana Martelli, Giorgio Butti, Paolo Gaetani, and Pietro Paoletti ¡MinilodiRicerche Farmacologiche "Mario Negri", Via Eritrea 62, 20157, Milan, Italy [M. G. C„C.C., R. F., L. M.J; and thèDipartimento di Chinirgia, Sezione di ClínicaNeurochirurgica, Centro "Enrico Grossi-Paoletti" per lo Studio e il Trattamento delle Neoplasie del Sistema Nervoso, Università ' di Pavía,27100 Paria, Italy {G. B.. P. G., P. P.]

ABSTRACT daily TXÃœ2(the hydrolysis product of TXA2) and PGE2, are produced by short-term cell cultures of human meningiomas Prostaglandin (PC) and thromboxane (TX) production by homogenates and gliomas (23). Using a highly selective method such as high of human intracranial tumors (33 gliomas, 32 meningiomas, six brain métastases)and "normal" brain (n = 26) from tumor-bearing patients resolution gas chromatography-mass spectrometry to measure was studied. l'<;(•',..,PGE2,PGD2, 6-keto-PGFi„(the hydrolysis product the five stable cyclooxygenase metabolites of AA, we have of PGIj) and TXB2 (the hydrolysis product of TXA2) were determined by preliminarily reported on prostanoid production by homoge high-resolution gas chromatography-mass spectrometry after ex vivo nates of human meningiomas and gliomas (24). In that study metabolism of endogenous arachidonic acid. Prostanoid profiles (relative we found high synthesis capacity and characteristic metabolic abundance of each metabolite) were different for gliomas and meningio profiles for each tumor, as we had already shown for murine mas, but similar for gliomas and their nontumoral counterpart, i.e., tumors such as Lewis lung carcinoma and M5076 ovarian "normal11 brain. Mean overall prostanoid production was significantly reticulosarcoma (6, 7). higher in gliomas (539 ±95) and meningiomas (523 ±69) than in We have now extended our observation to a larger number "normal11brain (198 ±23). Prostanoid synthesis significantly increased of patients with gliomas, meningiomas, and brain métastases. with anaplastic grade (glioblastomas > anaplastic astrocytomas > slow- growing astrocytomas > "normal11brain), while profiles did not substan We also present a comparative view of AA metabolic profiles in apparently nonpathological brain tissue, considered as the tially change (TXB2 was the most and 6-keto-PGFia the least abundant "normal" counterpart for gliomas. Correlations between pros product). Meningioma profiles showed no marked prevalence of any particular metabolite and no major differences between histológica! tanoid production and other biochemical and proliferative char subgroups. All brain métastasesfromdifferent carcinomas (n = 5) showed acteristics of each tumor are currently under investigation. a prevalence of TXB2 and PGE2 and very low PGD2 synthesis. MATERIALS AND METHODS INTRODUCTION Standards. PGF2„,PGF2„-D4,PGE2, PGE2-D4, PGD2, 6-keto- PGF,a, 6-keto-PGF1(I-D4, and TXB2 were kindly supplied by Dr. J. Several experimental and human tumors synthesize prosta- Pike of The Upjohn Co. (Kalamazoo, MI). TXB2-D8 was a kind gift of noids (1-5), which can be increasingly produced during tumor development (6-9). These cyclooxygenase metabolites of AA3 Dr. G. Galli (Università degli Studi di Milano, Milan, Italy). (unirai Samples. Specimens of intracranial tumors (33 gliomas, 32 (PGF2o, PGE2, PGD2, PGI2, and TXA2) may influence physio- meningiomas, and six métastases)werecollected during surgery. Spec pathological processes related to tumor development and dis imens of brain tissue (n = 26) were collected from some of these semination (e.g., cell proliferation, migration and adherence, patients who underwent lobectomy as part of a correct surgical treat host immunity, angiogenesis, hemostatic mechanisms) (1-5, ment. We will hereafter use the term "normal brain*1 to indicate a 10, 11). Cyclooxygenase or thromboxane synthetase inhibitors specimen which: (a) has been collected from tumor-bearing patients in may reduce tumor growth and metastasis, although there are an area apart from the tumor; (¿>)hasbeen proven free of tumoral cells controversial reports on this issue (1, 2, 7, 12-16). by histológica!examination of a section immediately adjacent to that used for AA metabolism. The capacity of tumors to grow, disseminate, and influence Ex Vivo Metabolism of Endogenous AA. The ex vivo evaluation of host homeostasis has in some cases been related to the produc endogenous AA cyclooxygenase metabolism has been described in tion of elevated amounts of some prostanoids. In human cancer, previous papers (24, 25). Briefly, samples (0.1-2 g) were rapidly frozen high content or synthesis capacity of selected prostanoids have in liquid nitrogen at the time of surgery and stored (-80°C) until been by some authors related to high met astatic potential (17), analysis. The frozen samples were directly homogenized in 10 volumes tumor size and met astatic spread (18), and irresponsiveness to of 50 mM phosphate buffer (pH 7.4). The homogenates were incubated for 15 min at 37°C,then spun at 15,000 x g for 45 min. The samples chemotherapy (19). Others found that although prostanoid were maintained at 4°Cduring homogenization and centrifugation. The synthesis of selected products was higher in malignant than in supernatants were kept at —¿20"Cuntilanalyzed. This procedure allows benign lesions, this did not correlate either with metastatic spread (20), or with clinical staging and prognosis (21), and the ex vivo metabolism of endogenous AA to give reproducible meta bolic profiles as reported previously (24, 25). was not associated with favorable prognosis (22). Quantitäten of AA Metabolites by HRGC-MS. The five stable me Data is scant regarding prostanoid production by human tabolites of AA (PGF2a, PGE2, PGD2, 6-keto-PGF,0, and TXB2) were intracranial tumors. Elevated amounts of prostanoids, espe- assayed by HRGC-MS and quantified by stable isotope dilution assay. Supernatants were spiked with deuterium-labeled internal standards Received 7/28/88; revised 11/23/88; accepted 11/30/88. The costs of publication of this article were defrayed in part by the payment (PGF2a-D4, PGE2-D4, 6-keto-PGF,a-D4, and TXB2-D8, 30 ng each; of page charges. This article must therefore be hereby marked advertisement in PGE2-D4 was used as internal standard for PGD2). Samples were accordance with 18 U.S.C. Section 1734 solely to indicate this fact. acidified (pH 3.5) with l N HC1 and applied to a Baker ( ',„SPEcolumn 'This work was supported in part by a grant from the Italian Ministry of (J. T. Baker Chemicals, Phillipsburg, NJ) prewashed with methanol Education (Rome, Italy, 1986) and from the National Research Council (87.01204.44). and 1 mN HC1. After washing with water and petroleum ether (10 ml 2To whom requests for reprints should be addressed. each), the column was eluted with methyl formate (1.5 ml). The eluate 3The abbreviations used are: AA, arachidonic acid; PG, prostaglandin; TX, was dried under an air flow and then derivatized to give the pentafluo- thromboxane; PGF!o-D4, 3,3'A,4'-*HrPGFia; PGEj-D4, 3,3',4,4'-2H,-PGE2; 6-keto-PGF,„-D4, 3,3',4,4'-2H4-6-keto-PGF,„; TXB¡-D8,5, 6, 8, 9, 11, 12, 14, robenzyl ester derivatives of AA metabolites and their deuterated ana 15-2H8-TXBi; HRGC-MS, high resolution gas chromatography-mass spectrom logues. The reaction was carried out by adding 30 n\ of a mixture of etry; El, electron impact; MCI, negative ion chemical ionization. pentafluorobenzyl bromide (Fluka, Buchs, Switzerland) and acetonitrile 1505 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1989 American Association for Cancer Research. PROSTANOID SYNTHESIS BY HUMAN BRAIN TUMORS

(1:2, v/v) and 10 p.\diisopropylethylamine (Fluka, Buchs, Switzerland) as preliminarily reported with fewer specimens from glioma- to the residue and heating at 40°Cfor5 min. The sample was thoroughly bearing patients (24). In the present set of data we obtained dried and the procedure repeated. The dried residue was then resus- similar profiles with "normal" brain from patients bearing pended in chloroform and applied to a Silica Bond-Elut column (An- gliomas, meningiomas, and métastases. alytichem International, Harbor City, CA), prewashed with chloroform. Glioma profiles were strikingly similar to those of their After washing with chloroform (10 ml), the column was eluted with 1.5 nonpathological counterpart, i.e., "normal" brain. This might ml chloroform:methanol (9:1, v/v). The eluate was taken to dryness under an air stream. indicate that the pattern of AA metabolism in tumoral cells is AA metabolites and their deuterated analogues were converted to strongly influenced by the enzymatic endowment of the tissue the methyloxime, trimethylsilyl ether derivatives with 50 ¿tlmethylox- from which they originate, rather than being specific to neo- ime hydrochloride (Pierce Chemicals, Rockford, IL) (30 min at 60°C) plastic cells in general. Mean synthesis capacity varied widely followed by 50 n\ bis(trimethylsilyl)trifluoroacetamide (Fluka, Buchs, in different specimens cf gliomas, possibly being influenced by Switzerland) (15 min at 60°C).AA metabolites were analyzed by factors such as tumor size, kariotypic heterogeneity, presence HRGC-MS in the selected ion-monitoring mode. All samples were of necrosis, edema, or hemorrhage. Nevertheless, average pros- analyzed in the El mode, and some selected samples were also analyzed tanoid production (539 ±95ng/g) was significantly higher than in the NICI mode to further confirm the identity of the compounds. in "normal" brain tissue (198 ±23ng/g). The increased capac A fully computerized VG TS-250 mass spectrometer equipped with a Hewlett-Packard 5890 gas Chromatograph was used. EI-MS operating ity of neoplastic cells to produce prostanoids has already been conditions were: electron energy, 22.5 eV; ionizer temperature, 200°C. seen in a number of human tumors (22, 26-29). For El-selected ion monitoring the following ions were recorded: m/z When different histological subgroups of gliomas were ex 589 for PGF2„and m/z 593 for PGF2o-D4; m/z 461 for PGE2 and amined (Table 1), prostanoid production was found to increase m/z 465 for PGE2-D4; m/z 544 for PGD2 and 6-keto-PGFi„and with anaplastic grade (from "normal" brain to glioblastomas). m/z 548 for 6-keto-PGF|i>-D4; m/z 301 for TXB2 and m/z 304 for Glioblastomas synthesized significantly more prostanoid than TXB2-D8. For NICI-selected ion monitoring, carboxylate anions (M- slow-growingastrocytomas and "normal" brain. Some changes 181) were recorded. HRGC operating conditions were: 25 m CP Sil 5 in the proportions of each metabolite were noted when ana- CB (Chrompack, The Netherlands) fused silica capillary column (0.32- plastic features differed, although the overall profile was not mm I.D., 0.13-Mm film thickness), oven temperature programming 160-300'C (1°Cisothermal, then 15°C/min),spiitless injection mode, substantially altered (Table 1). TXB2 and 6-keto-PGFia were, helium as carrier gas. respectively, the most and least abundant products, regardless Results are expressed as AA metabolite synthesis potential (ng/g) of the grade of anaplasia. These findings confirm those reported and profile (percentage of each metabolite formed). earlier with a smaller number of cases (24). However, this set of data did not confirm the previous observation that the increased prostanoid synthesis in glioblastomas seemed to be RESULTS AND DISCUSSION preferentially directed toward TXB2. The AA metabolic profile in meningiomas as a class was Cyclooxygenase AA metabolism (overall and relative pros- markedly different from that of gliomas (Fig. 1). PGE2, PGÖ2, tanoid production) by human intracranial tumors and "normal" and 6-keto-PGFia relative amounts were higher (P < 0.01, i brain tissue (a definition is given under "Materials and Meth ods") is shown in Fig. 1. AA metabolism by "normal" brain test) in meningiomas than in gliomas, while the opposite was found for TXB2 (P < 0.01, t test). Table 2 shows prostanoid showed a characteristic profile, with a net prevalence of TXB2 production in different histological subclasses of meningiomas. and low levelsof 6-keto-PGFla (the hydrolysis product of PGI2), Generally, absolute and relative synthesis of each product were similar for all subclassesbut for anaplastic meningiomas, which tended to synthesize lower amounts of TXB2 (statistically sig nificant difference only versus psammomatous meningiomas). The small number of observations does not allow any specula tion on a possible biological significance of the different pros tanoid profile of anaplastic meningiomas. We could not com pare meningiomas with "normal" tissue as we did for gliomas, since for ethical reasons it was not available. The biological relevance of increased prostanoid production by tumors has not been clearly established. However, ongoing studies by our groups preliminarly show that in gliomas as well as in meningiomas the overall capacity of prostanoid synthesis correlates directly with the proliferative capacity of the tumor. Moreover, as a consequence of an increased AA metabolism, 1000 - certain tumors could synthesize abnormal amounts of selected * prostanoids which might facilitate or impair the growth and 500-*** dissemination of the tumor itself or affect the host's defense mechanisms (1-5). In this respect, it is interesting to note some relative proportions of prostanoids found in the rapidly growing "NORMAL"BRAIN GLIOMAS MENINGIOMAS infiltrating gliomas compared to the slow-growing benign me ningiomas. In fact, gliomas synthesize higher relative propor Fig. 1. Total AA metabolite synthesis (sum of TXB2, PGE2, PGD2, 6-keto- tions of TXB2and lower relative amounts of 6-keto-PGFIo and PGF,„,and PGF2„;bottom) and AA metabolic profiles (% of each metabolite formed; top) by human "normal" brain (n = 26), glioma (n = 33), and meningioma PGD2 than meningiomas. TXA2 (the active unstable precursor (n = 32) homogenates. (A definition for "normal" brain is given under "Materials and Methods"). Tumor specimens were collected at surgery, frozen in liquid of TXB2)has been shown in some experimental studies to favor nitrogen, homogenized, and incubated at 37'C to allow metabolism of endogenous tumor growth and spread (14, 30, 31), while the opposite has AA. Bars, mean ±SE; **, p < 0.01 versus "normal" brain (Tukey's test). been reported for PGD2 (32-35) and PGI2 (the active unstable 1506

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1989 American Association for Cancer Research. PROSTANOID SYNTHESIS BY HUMAN BRAIN TUMORS Table 1 AA metabolites in "normal" brain" and gliomas

total)Histology"Normal" AA metabolite ng/g (% of AA metabolites198 brain (n = 26) ±14' ±219±4 ±4 1 ±6(26 ±23 (41 ±3)c (15 ±2) (4±1) ±2) Slow-growing astrocytomas (n = 8) 174 ±35 22 ±8 4 ±0,5 33 ±11 253 ±52 (66 ±6) (9 ±2) (8 ±2) (3±1) (13 ±2) Anaplastic astrocytomas (n = 11) 182 ±35 73 ±22 56 ±14 16±5 69 ±12 455 ±93 (50 ±5) (16 ±3) (12 ±2) (4±1) (17 ±3) Glioblastomas (n = 14)TXB287 314 ±72" 172 ±84' 99±31r 45 ±IS'' 137±29/J'* 768 ±196*' (42 ±3)PGE225 (19 ±3)PGD229 (11 ±2)6-keto-PGF,.7±(8 ±2)PGF,„51(20 ±3)Total °Adennition for "normal" brain is given under "Materials and Methods." '' Mean ±SE. Data were analyzed by ANOVA. Statistical differences were determined by Tukey's multiple comparison test. ' Numbers in parentheses, mean relative amount. à P < 0.01 versus "normal" brain. ' P < 0.05 versus slow-growing astrocytomas. *P< 0.01 versus slow-growing astrocytomas. * P < 0.05 versus "normal" brain. * P < 0.05 versus anaplastic astrocytomas.

Table 2 AA metabolites in meningiomas (ng/g)Histological AA metabolite AA subgroupsMeningothelial metabolites444 (n = 11) ±37° ±23(22 ±31(22 ±29 ±16(H ±126 (27 ±3)» ±2) ±4) (12 ±4) ±2) Fibroblastic (n = 9) 177 ±47 85 ±19 102 ±42 105 ±34 57 ±7 527 ±113 (31 ±3) (18 ±3) (16 ±3) (19 ±5) (15 ±3) Transitional (n = 4) 155 ±68 146 ±67 95 ±30 98 ±38 79 ±33 574 ±214 (26 ±7) (25 ±5) (18 ±2) (17 ±6) (14 ±2) Psammomatous (n = 4) 318 ±102 229 ±78 81 ±43 118±55 92 ±32 837 ±244 (34 ±5) (25 ±3) (15 ±7) (14 ±4) (12 ±2) Anaplastic (n - 4)TXB2122 81 ±48C 161 ±82 52 ±17 33 ±14 40 ±13 367 ±134 (19 ±7)PGE293 (36 ±9)PGD2105 (16 ±4)6-keto-PGF;a58(16 ±12)PCF,.66 (13 ±2)Total " Mean ±SE. Data were analyzed by ANOVA. Statistical differences were determined by Tukey's multiple comparison test. " Numbers in parentheses, mean relative amount. c P < 0.05 versus psammomatous. precursor of 6-keto-PGFia) (14, 30); however, in other experi Our preliminary observation of high TXB2 and PGE2 and mental models, straightforward effects of these metabolites low PGD2 synthesis in carcinoma métastases,although limited could not be demonstrated (7, IS, 16). to a small number of cases, merits further investigation to We also examined six cases of brain métastases(three lung establish whether the potential of cells to metastasize to the carcinomas, one breast carcinoma, one gastric carcinoma, one brain can be influenced by their capacity to synthesize selected melanoma). Prostanoid synthesis capacity and profiles varied AA metabolites. even in métastasesof similar origin (lung carcinomas). Never Although our measurements describe the potential capacity theless, common features of the five carcinoma métastaseswere of tumors to synthesize prostanoids, recent findings suggest high TXB2 synthesis (range, 98-318 ng/g; mean ±SE, 188 ± that these indirect measurements may reflect a real in vivo 36 ng/g) and low PGD2 production (range, 11-42 ng/g; mean situation. In patients with ovarian cancer, a strong correlation ±SE, 20 ±6). Other prostanoids were formed in variable has in fact been noted between urinary levels and in vitro tumor production of 6-keto-PGFi„ (21). Preliminary data from our amounts, with an overall synthesis ranging from 167 to 2163 ng/g, the average profile being TXB2 > PGE2 > PGF2o > 6- laboratory shows increased urinary levels of thromboxanes in keto-PGFia > PGD2. The single case of melanoma metastasis mice bearing the thromboxane-producing M5076 ovarian re- had very low AA metabolism (total prostanoid synthesis 43 ng/ ticulosarcoma (7). If consistent shifts in urinary prostanoid profiles could be demonstrated in patients with different tumors g) and a net prevalence of TXB2 (54%) over the other metabo with well-characterized metabolic profiles, this might provide a lites. new tool for diagnosis and monitoring of malignancy. As far as the significance of these metabolites for the expres sion of malignancy in human tumors, a positive correlation has been found for breast carcinomas between synthesis of PGE2 ACKNOWLEDGMENTS and metastatic capacity of the tumoral lesions (17). Karmali et We thank Judith Baggott and the stall of the Gustavus A. Pfeiffer al. (18) found that TXB2 synthesis by breast cancer correlated Memorial Library who helped prepare the manuscript. with tumor size and the number of positive nodes. TXB2 and PGE2 but not 6-keto-PGFi0 contents were significantly higher REFERENCES in metastatic than in benign ovarian cancer tissue (29). In contrast, PGD2 synthesis was inversely correlated to the met 1. Honn, K. V., Bockman, R. S.. and Marnett, I J. Prostaglandins and cancer; a review of tumor initiation through tumor metastasis. Prostaglandins, 21: astatic capacity of two B16 melanoma cell lines (32). Also, 833-864, 1981. PGD2 may inhibit the metastatic process (33), while TXA2 and 2. Levine, L. Arachidonic acid transformation and tumor production. Adv. Cancer Res., 35:49-79, 1981. PGE2 may favor dissemination (10, 14, 30, 36) although this is 3. Powles, T. J., Bockman, R. S., Honn, K. V., and Ramwell, P. (eds.), controversial (7, 15, 16, 37, 38). Prostaglandins and Cancer. New York: Alan R. I ¡ss.1982. 1507

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Maria Grazia Castelli, Chiara Chiabrando, Roberto Fanelli, et al.

Cancer Res 1989;49:1505-1508.

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