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Inhibition of CA 125, a Novel High Molecular Weight Glycoprotein

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Inhibition of CA 125, a Novel High Molecular Weight Glycoprotein Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 1988 Inhibition of CA 125, a Novel High Molecular Weight Glycoprotein Expressed by an Ovarian Carcinoma Cell Line, OVCA 433, is Related to Glucocorticoid Effects of Altered Cell Growth, Morphology, and Growth Pattern Ellen Michele Weinstein Yale University Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation Weinstein, Ellen Michele, "Inhibition of CA 125, a Novel High Molecular Weight Glycoprotein Expressed by an Ovarian Carcinoma Cell Line, OVCA 433, is Related to Glucocorticoid Effects of Altered Cell Growth, Morphology, and Growth Pattern" (1988). Yale Medicine Thesis Digital Library. 3295. http://elischolar.library.yale.edu/ymtdl/3295 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. ^PILE UNIVERSITY LIBRARY YALE MEDICAL LIBRAPY 11 . Digitized by the Internet Archive in 2017 with funding from The National Endowment for the Humanities and the Arcadia Fund https://archive.org/details/inhibitionofca1200wein YAIE MiilCHi UBRWV S' w * 7'i4i f, if „■ 1 ■ , .— '♦ '.*»<. ijM .jJi(i| ii INHIBITION OF CA 125, A NOVEL HIGH MOLECULAR WEIGHT GLYCOPROTEIN EXPRESSED BY AN OVARIAN CARCINOMA CELL LIME, OVCA 433, IS RELATED TO GLUCOCORTICOID EFFECTS OF ALTERED CELL GROWTH, MORPHOLOGY, AND GROWTH PATTERN A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine by Ellen Michele Weinstein (Med ub 4Yf2, ABSTRACT INHIBITION OF CA 125, A NOVEL HIGH MOLECULAR WEIGHT GLYCOPROTEIN EXPRESSED BY AN OVARIAN CARCINOMA CELL LINE, OVCA 433, IS RELATED TO GLUCOCORTICOID EFFECTS OF ALTERED CELL GROWTH, MORPHOLOGY, AND GROWTH PATTERN Ellen Michele Weinstein 1988 OVCA 433 human ovarian carcinoma cells treated with lxlO"^M dexamethasone exhibit markedly decreased expression of CA 125, a nonmucinous, high-molecular weight (M2-=220,000) tumor-associated antigen as determined by an indirect immunoperoxidase technique with OC 125, a monoclonal antibody (MAb) recognizing the CA 125 determinant. Inhibition of CA 125 expression parallels dose-dependent glucocorticoid-induced effects leading to 32% growth inhibition and the appearance of cell morphological alterations, including enlargement, rounding, flattening, and multinucleation. CA 125 inhibition and altered cell growth appear to be events mediated through glucocorticoid receptors (GR) since other classes of steroid hormones, including aldosterone, estradiol, progesterone, and dihydrotestosterone fail to produce these effects. Furthermore, direct antagonism of CA 125 in vitro via functional blockade of cell surface bound glycoprotein with OC 125, anti-CA 125 MAb, produces 70% growth inhibition and profound alterations in cell growth pattern. OVCA 433 cells growing in OC 125-treated cultures become enlarged, markedly polygonal and assume neat, hexagonal arrays. Morphological alterations occur in a concentration-dependent manner at 3, 10, and 30 ug/ml with approximately 25%, 70%, and 100% of cells affected, respectively. These results suggest decreased cell surface CA 125 expression may mediate glucocorticoid-induced growth inhibition and morphological alterations, and suggest that the CA 125 determinant plays an important role in the control of ovarian carcinoma cell growth. \ -S ' I /r f - n • ?■>- ' . » -■ X- -.^ .-..a- ■ .5' "or^c- I - • . 1 ^ IrTI’j ■ > '"•»■•'. r A'* '' ‘.i : i ‘- 'l; f. * :.• 3 1 ::?- l JJlil LS-/.-, r j ._ • * -V ■' ^ c ■'ii'4.- .■* I • qc'nT-:rii,f I I ^ ^ r!A.**> Y-' c ^ r« Hvj \ * r ’ • ^ - r J ^ * I m K iitr I _ • * : • i i-»■'(•. v^*:oAoxij p -■■rj t 5''*T, U" •-' . ' ^ ' : <■. T ' o J .aflJ • .- - ■ »-r -■ r': i: r-n xor:' X, .Z'l •.'T'j '.: s : f : \ ... .. jg ^ : v’.i -; r J ium. nnx <. 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GLUCOCORTICOID-INDUCED GROWTH INHIBITION .... 10 Glucocorticoids Alter Cell Growth . 10 Primary Events Regulate Cell Growth . 10 Malignant Cells Exhibit Aberrant Response to Normal Growth Regulatory Processes ... 11 Glucocorticoids Induce Growth Arrest in Neoplastic Cells at Defined Restriction Points. 12 Glucocorticoids May Regulate Cellular Response to Autocrine Growth Factors . 13 II. TUMOR-ASSOCIATED ANTIGENS . 18 Many Tumor-Associated Antigens are Carbohydrate Stuctures . 18 Carbohydrate Synthesis May Be Aberrant in Neoplastic Cells . 19 Immunopathological Correlations of CA 125 Expression. 22 MATERIALS AND METHODS. 27 RESULTS. 31 Dexamethasone-induced morphological alterations . 31 Immunocytochemical detection of CA 125. 31 Immunolocalization of CA 125 Determinant . 33 Dexamethasone effect on cell growth . 34 Antagonism of CA 125 determinant. 34 Specificity of the OC 125 effect. 35 Determination of OC 125 effect on cell growth ... 36 DISCUSSION. 38 ACKNOWLEDGEMENTS . 47 APPENDIX 1. 63 REFERENCES. 64 S' i-* p ■'■ 10 rtvT.TfiT 't ..... 3.qtn*ircma 01 \}rvrt-r.'GOTn'jrv:)rj<?L^icu -i "* r %c I M*,-* % J: '^*.!^ 1 i ^ ^ O ^ j 1 *>» * -r f ■#-< o^ ^ =:rQat^3- j, -.-. C .4. w ;snuilart 111 ^*1-'.'* .:.■ ••'■ ' -:.• f’W- i ■' ' A.Vri • .Q'^C'tJU ! =} no; TOi“Tt?r'- i j toi T ■ 1.. ''■.? A . - . 72:ir:,Ip‘l I M j ^ . '■ C ' c/ *r> ^ - b •' • 7t.‘. »V' ‘ < r> 0 f O r f T ^ iLii-T. u-J ■Se.'JC'Afai'r'^l ..... ^;:;i'.S'.-..:OC-ac:A-.>i'<irtU’i .II a4 :i *3 A 1 ' ji ^ t - A iji ’iv A.-Ajv:-'.-- .J^*:'^l6^ ox fv. :r:L- ;■ ..Td •'.ri >•:£:•* J- • Y''- A* -■ i a 0 . s ".. !c.'J r. v.-.Ta.-..ii f'c; , ., -’•■ij.-.r. ■ ■ : o;". 1 sr^, --o :, Mi-uT.-ittrsnijs:-;!. , . ■ . : >Oi A-I-* :'.■; Xvi TS .' atfA iiJJkm^Z'APf ,■ ci’T.W.Tr . .. W .."i J.-. i ^ •- c ^ t ' ■.'. ^:-. :cl.:7r: c? • :-•<•* 7/ *■''^■^ A'> ■ r- rfO f ::»■-$.A r t.i«X^^Xp‘rtG!t-”rT.I, • >«•,.• I O ? ‘ 'v V-> 44^'^'tc* £Mise».;;. a*Cl » r • * c•.-at:. --ili -4-3 C',*'' lae ‘t:\iiiis. X tjft. - • - . - 1 . ilr'-f -p ■ l^- A rr-! ■• .A .-.'{%- ^ r rn' ) c, rt^i *rBn-^er,i at: . i '.v^r..r :A .I-'X4 .t^'.r-CTS'^’L* J- ‘"Y 4 INTRODUCTION In 1975, Kohler and Milstein proposed a method for fusion of myeloma and murine spleen cells to create hybridomas capable of continous production of specific antibodies in vitro^. termed monoclonal antibody (MAb). Murine monoclonal antibody technology has significantly impacted the direction of clinical diagnosis and management as well as introduced an unlimited supply of molecular and functional probes for study of cellular and molecular processes. One outgrowth of this innovation was the recognition that tumor cells and cells neoplastically transformed via viral or chemical induction, express cell surface molecular or macromolecular components which are often antigenically distinct from the normal cell surface repertoire. A number of murine monoclonal antibodies have been prepared against a variety of human neoplasms including colorectal, pancreatic, endometrial, ovarian, and breast carcinoma as well as melanoma and osteogenic sarcoma. The specificity provided by monoclonal antibodies for distinguishing neoplastic from normal tissue promises to revolutionize cancer diagnosis and therapeutics; monoclonal antibodies such as CA 125 have, in many cases, already become useful adjuncts to clinical diagnosis and management. CA 125, an ovarian carcinoma tumor-associated antigen. ' • 'f *>* t ,-/• t . ^ ,M>r- *'y..,*t". f'J'J’J nJ V • ' ■* ■•■'- -ly/u :o <lx>Xm*^VL ,*'■■' -j ' i*; • ■'•'>••.'.••*1 •'I '-‘i;'- 1 >, ,i ■« f t-*«r 2» ,;. ■ ‘q ; i •' ••• /' ■»' ‘ rv--i i nt^v -vt?! '- • ■■' ■- -■ ‘ i * 4. *’ *r.J ' Jb'S'il' '. ' ■ ■ ■' !■' 1C £iVC * ■ '•-* '■' ,'J 'Ti-p r '■nfe r,^‘. ■ •'•■ '•'- ■-■■1 -.'j : •: /. t] r ' • ^ ' ' ‘ • ,.i f.f •■ . .*51 'N*o c. .5 . ^ 1.^ I i i . t- ■ ’ ' VC . V. 1. 5. .T” ..• -■• . 'L ■ , n^ifT ' ‘‘i ’ r-'T rq.. .>CX_‘paJj|Bi^ ■ ac-ISC r C tWi^VI^'3 Vl.‘--u-IX: • ivc • c-- vj jt iio«us »9! bcxi. qi:T,:jn'^cr**.r t-’.a b'‘tr ..n.-'' 1:=-••* ■'ij i.. c? 3 .''c it;.-■ {?.-<! *^0^01^ ,rvj,rT ;: Curi* rr*c-’=..g&^ Svfe-’rn; 1rX’ii.'xfV© nt> .-r'u: A-J 5 is a high molecular weight glycoprotein (Mj-=220,000) expressed by 80% of nonmucinous epithelial ovarian carcinoma cells.2^3 QQ 125, a murine monoclonal IgGl bearing a recognition site for the CA 125 epitope, was raised against OVCA 433 cells, a human serous cystadenocarcinoma cell line.^ OC125 recognizes a distinct determinant shared by malignant ovarian carcinoma cells and fetal coelomic epithelium and is not found in detectable amounts in either adult or fetal ovary.On this basis, CA 12 5 represents an oncofetal protein which may play a role in the complex processes regulating cell proliferation and differentiation.
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