Indian Journal o f Cllnlcal Blochemlstry 1992, 7(2) 81-88

INTRACELL~

PROTEINS AS TUMOR MARKERS

ALPANA GUPTA § T MALATI* AND P D GUPTA* Department of Biochemistry, Nizams I n s t i t u t e of Medical Sciences, H y d e r a b a d - 500 482. I n d i a *Centre for Cellular & Molecular Biology. H y d e r a b a d - 500 007. India.

INTRODUCTION D u r i n g m a l i g n a n t t r a n s f o r m a t i o n o f cells, t h e r e is a c h a o s in t h e p r o g r a m m e d gene expression. C e r t a i n cells w h i c h are fully differentiated s u c h as h e p a t o c y t e s in w h i c h a l b u m i n is the m a r k e r protein, s t a r t p r o d u c i n g AFP-and oncofetal antigen, w h e n t h e y b e c o m e c a n c e r o u s . In adult s u b j e c t s , if o n e d e t e c t s AFP in t h e s e r u m , t h e r e is a c h a n c e t h a t t h e i n d i v i d u a l m a y be suffering f r o m h e p a t o c e l l u l a r c a r c i n o m a ( 1,2). Some of t h e gene p r o d u c t s w h i c h are n o t e x p r e s s e d or e x p r e s s e d in very low a m o u n t s in n o r m a l h e a l t h y cells, m a y be o v e r e x p r e s s e d a f t e r m a l i g n a n t t r a n s f o r m a t i o n . S u c h s u b s t a n c e s are secreted in the s e r u m a n d c a n be u s e d to d i a g n o s e malignancies. T h u s , t u m o r m a r k e r s c a n be defined as a biochemical s u b s t a n c e p r o d u c e d by t h e t u m o r w h i c h w h e n p r e s e n t in significant detectable a m o u n t s , i n d i c a t e s t h e p r e s e n c e of a c a n c e r (3-6). E s s e n t i a l l y , a n y m o l e c u l a r species p r o d u c e d in a b n o r m a l (low or high) a m o u n t s or u n d e r a b n o r m a l c i r c u m s t a n c e s m a y b e c o m e u s e f u l a s a diagnostic tool. Biochemically, t u m o r m a r k e r s are u s u a l l y c o n j u g a t e d p r o t e i n s w h i c h m a y be p r e s e n t in m i n u t e q u a n t i t i e s in t h e n o r m a l h e a l t h y individual, b u t t h e elevated levels of t h e s e s u b s t a n c e s indicate m a l i g n a n c i e s . Excellent reviews are available on secretory proteins w h i c h a c t a s t u m o r m a r k e r s (7,8), however, t h e u s e o f i n t r a c e l l u l a r p r o t e i n s as c a n c e r m a r k e r s is n o t in vogue, therefore, very little i n f o r m a t i o n is available a b o u t t h e m . The scope of this review is to provide w h a t e v e r little i n f o r m a t i o n available a b o u t i n t r a c e l l u l a r proteins w h i c h c a n be u s e d a s t u m o r m a r k e r s a n d m e n t i o n t h e i r a p p l i c a t i o n s in t u m o r biology. Applications of tumor markers T u m o r m a r k e r s h a v e a diverse set o f applications right from d e t e c t i o n o f c a n c e r s to t h e i r t h e r a p y . I m p o r t a n t a p p l i c a t i o n s i n c l u d e their ability to provide v a l u a b l e i n f o r m a t i o n r e g a r d i n g t h e s t a g i n g o f t u m o r s . M a r k e r s c a n also be u s e d to detect m e t a s t a s i s by r a d i o i m r n u n o m e t h o d s (9). T u m o r m a r k e r s h e l p in prognosis or t r a c k i n g t h e b e h a v i o u r o f a t u m o r . The m a r k e r levels, h i g h or low, i n d i c a t e w h e t h e r a t u m o r is progressing or regressing respectively. A c c o r d i n g to t h e t u m o r type a n d its b e h a v i o u r , a n a p p r o p r i a t e m e t h o d of t h e r a p y c a n be d e c i d e d u p o n , e i t h e r c h e m o t h e r a p y , r a d i o t h e r a p y , r e s e c t i o n of the t u m o r or a c o m b i n a t i o n o f a n y o f t h e s e m e t h o d s . The 11kelLhood o f r e s p o n s e to t h e m o d e of t r e a t m e n t c a n also be p r e d i c t e d b y e v a l u a t i o n o f t h e t u m o r m a r k e r (8). The m o s t fruitful application o f t u m o r m a r k e r s is monitoring t h e t u m o r activity a n d efficacy of t r e a t m e n t . This h a s b e e n realized m o s t c o n s i s t e n t l y i n g e s t a t i o n a l t r o p h o b l a s t i c t u m o r s ( c h o r i o c a r c i n o m a s ) in w o m e n (10) a n d n o n s e m u n o m a t o u s g e r m cell t u m o r s i n m e n (11 ). Besides t h e above m e n t i o n e d applications, t h e c o n c e n t r a t i o n o f a t u m o r m a r k e r reflects a a d y n a m i c b a l a n c e r e p r e s e n t i n g t h e c o m b i n a t i o n of t u m o r activity a n d m a r k e r t u r n o v e r . However, t h e r e is

A d d r e ~ for C o m m u n i c a t i o n Dr P D G u p t a C e n t r e for Cellular & Molecular Biology, Telephone : 0 0 - 9 1 - 8 4 2 - 8 ~ 2 2 4 1 Telex : 0 4 2 5 - 7 0 4 6 CCMB IN, F a x : 0 0 - 9 1 - 8 4 2 - 8 5 1 1 9 5

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n o t a u n i v e r s a l c o r r e l a t i o n b e t w e e n t u n m o r size a n d m a r k e r c o n c e n t r a t i o n . The u l t i m a t e a p p l i c a t i o n o f t u m o r m a r k e r s is to target a n t i b o d y b o u n d cytotoxic a g e n t s or t h e p a t i e n t ' s o w n i m m u n e cells to preferentially control or d e s t r o y m a l i g n a n t cells while m i n i m i z i n g d a m a g e to n o r m a l cells. In o t h e r words, t h e c o n c e p t of i m m u n o t h e r a p y c a m e t h r o u g h t u m o r m a r k e r s in cancer management.

Classification of Tumor markers D e p e n d i n g o n w h e t h e r the m a r k e r protein is s e c r e t e d by t h e t u m o r cells or not, t u m o r m a r k e r s c a n be classified into two m a i n types (12): (I )

T u m o r derived p r o d u c t s ; a n d

(2)

Tumor associated products.

T u m o r derived p r o d u c t s or molecules p r o d u c e d by the t u m o r s are f u r t h e r s u b d i v i d e d into two types: (a) S y n t h e s i z e d p r o d u c t s ; a n d (b) Metabolically active s u b s t a n c e s .

S y n t h e s i z e d products may be: (i) Oncofetal antigens: m a r k e r s like (x-fetoprotein (5,13) a n d C a r c i n o e m b r y o n i c a n t i g e n (6,14) belong to this class. They are glycoproteins s y n t h e s i z e d in t h e e m b r y o n a l s t a g e w i t h a m i n i m u m v a l u e r e a c h i n g a t a d u l t h o o d . Only in c e r t a i n specific m a l i g n a n c i e s , t h e i r level in t h e s e r u m is i n c r e a s e d significantly in a d u l t s . (II) Ectopic products : The modified m e t a b o l i s m of t u m o r cells r e s u l t i n g from i n c r e a s e d cell proliferation l e a d s to i n c r e a s e d s y n t h e s i s of various e n z y m e s w h e n c o m p a r e d to n o r m a l cells. M a r k e d i n c r e a s e in t h e activity of s o m e e n z y m e s for glycolysis, b i o s y n t h e s i s of n u c l e i c acid a n d p r o t e i n s are c h a r a c t e r i s t i c of a m a l i g n a n t metabolic process. As a r e s u l t of low specificity however, t h e i r d i a g n o s t i c value for t u m o r d i a g n o s i s is limited. (iii) Oncoplacental antigens : H u m a n chorionic g o n a d o t r o p i n a n d p r e g n a n c y specific B-1 glycoprotein (SPI) are b e s t k n o w n m e m b e r s of this series ( 15-17). (2) Tumor associated products : These are factors a c c o m p a n y i n g t h e m a l i g n a n t p h e n o m e n o n . A l t h o u g h this c l a s s of m a r k e r s have low specificity, however, as a d d i t i o n a l facultative m a r k e r s t h e y c a n i n d i c a t e m a l i g n a n t d i s e a s e s a n d provide a d d i t i o n a l i n f o r m a t i o n d u r i n g time c o u r s e m o n i t o r ing. This c l a s s i n c l u d e s q u a n t i t a t i v e l y altered s e r u m proteins s u c h a s ferritin a n d B 2 m i c r o g l o b u l i n (18-20) a n d i n t r a c e l l u l a r p r o t e i n s s u c h as cytoskeletal proteins (21-23) e n z y m e s (kinases, p h o s p h a t a s e s ) w h i c h are involved in p h o s p h o r y l a t i o n of r e g u l a t o r y p r o t e i n s (24,25), e n z y m e s s u c h a s t r a n s g l u t a m i n a s e (26) w h i c h help in protein t r a n s a m i n a t i o n (cross-linking of proteins) a n d g l y c o s y l a t i o n (27). Src gene family o n c o g e n e p r o d u c t s c a n also be i n c l u d e d a s i n t r a c l l u l a r p r o t e i n t u m o r m a r k e r s (28).

Specificity of tumor markers S o m e t u m o r m a r k e r s are believed to be specific for c e r t a i n c a r c i n o m a s b e c a u s e t h e y are p r o d u c e d by t h o s e t u m o r s a n d h e n c e are u s e d to diagnose t h a t p a r t i c u l a r m a l i g n a n c y . Table 1 below o u t l i n e s s o m e o f the t u m o r m a r k e r s a n d the c a n c e r s for w h i c h t h e y are specific (8).

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Table- 1 Tumor m a r k e r s

T y p e o f t u m o r for w h i c h s p e c i f i c

Carinoembryonic a n t i g e n (CEA) Alphafetoprotein {AFP)

Well differentiated t u m o r s of t h e large bowel. Hepatocellular carcinomas and nons e m i n o m a t o u s g e r m cell t u m o r s . Choriocarcinomas

~-Human chorionic gonadotropin (~-HCG) Prostate specific a n t i g e n (PSA} a n d Prostate alkaline p h o s p h a t a s e (PAP) Calcitonin Carcinoma a n t i g e n 19-9 (CA 19-9) Carcinoma a n t i g e n 125 (CA 125) ~2- microglobulin Creatine k i n a s e (CK} CK-BB Neuron specific e n o l a s e (NSE) Lacatate d e h y d r o g e n a s e (LDH) Arginine v a s o p r e s s i n (AVP), Neurophysin, Parathyroid h o r m o n e (PTH), B o m b e s i n Glycosyl t r a n s f e r a s e s Pancreatic oncofetal a n t i g e n {POA) Tissue p o l y p e p t i d e a n t i g e n

Prostate c a n c e r Medullary thyroid c a r c i n o m a Epithelial t u m o r s of t h e p a n c r e a s , c o l o r e c t u m and stomach Non-mucinous ovarian tumors Multiple m y e l o m a s S m a l l cell l u n g c a n c e r (SCLC}, b r e a s t a n d prostate N e u r o e n d o c r i n e t u m o r s i n c l u d i n g SCLC G e r m cell t e s t i c u l a r t u m o r s

Lung Ova .ry, breast, p a n c r e a s Pancreas Bre,: ~ celor.,, l u n g

Some anomalies The above listed m a r k e r s have been f o u n d to be elevated in t h e p a r t i c u l a r c a r c i n o m a s m e n t i o n e d . The p r o b l e m in diagnosis is t h a t n o n m a l i g n a n t d i s e a s e s c a n also be a s s o c i a t e d with the s a m e m a r k e r a b n o r m a l i t i e s . A m a r k e r c a n also be elevated in more t h a n one type o f m a l i g n a n c y , m a k i n g a d i a g n o s i s b a s e d solely o n the m a r k e r a s s a y n o t reliable. For e x a m p l e , h i g h C E A levels m a y i n d i c a t e t h e p r e s e n c e of either g a s t r o i n t e s t i n a l t r a c t cancer, l u n g cancer, c a n c e r o f t h e female genital t r a c t or h e a d a n d n e c k c a n c e r s (29). A n o t h e r d r a w b a c k of d e t e c t i n g c a n c e r s by t u m o r m a r k e r a s s a y s is low sensitivity of the a s s a y , w h i c h m a y be high for a d v a n c e d or m e t a s t a t i c c a n c e r b u t u s u a l l y is less t h a n 50% for early or localized cancer. Epithelial tumor markers Recently, by u s i n g diagnostic h i s t o p a t h o l o g y a n d i m m u n o h i s t o c h e m i s t r y , m o l e c u l a r comp o n e n t s t h a t are specifically e x p r e s s e d in epithelial cells have b e e n recognised. T h e s e specific c o m p o n e n t s have a c q u i r e d great i m p o r t a n c e in t u m o r biology a n d p a t h o l o g y a n d h a v e b e e n d e s i g n a t e d as "epithelial differentiation markers". S u c h m a r k e r s have two m a i n a p p l i c a t i o n s : (a) in d i s t i n g u i s h i n g epithelial from non-epithelial t u m o r s ; a n d (b) in d i s t i n g u i s h i n g the type of epithelial t u m o r . I m p o r t a n c e is n o w being a t t a c h e d to epithelial differentiation m a r k e r s s u c h a s c a n c e r associated a n t i g e n [19-9] (30-32} a n d c a n c e r a s s o c i a t e d a n t i g e n [125] (32-36), epithelial m e m -

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b r a n e a n t i g e n [EMA] (37), t i s s u e polypeptide a n t i g e n [TPA] (38), k e r a t i n s (39-48), s q u a m o u s cell c a r c i n o m a a n t i g e n [SCCA] (49-53) a n d N e u r o n specific e n o l a s e [NSE] (54-56). In c o n t r a s t to o t h e r epithelial m a r k e r s described above, k e r a t i n f i l a m e n t s are u s u a l l y u n i f o r m l y d i s t r i b u t e d a m o n g c a r c i n o m a cells a n d also, the degree of stability of k e r a t i n e x p r e s s i o n in t u m o r s is r e m a r k a b l y high. Therefore, k e r a t i n is also a reliable m a r k e r for (a) u n d i f f e r e n t i a t e d a n d a n a p l a s t i c c a r c i n o m a s , (b) d i s p a r a t e l y growing i n f l t r a t i n g c a r c i n o m a cells a n d (c) for m e t a s t a s i z i n g single c a r c i n o m a cells in s u s p e n s i o n . TPA w h i c h is r e g a r d e d as b e i n g a m a r k e r of proliferation, is a m i x t u r e of proteolytic f r a g m e n t s c o n t a i n i n g t h e relatively s t a b l e a - h e l i c a l rod d o m a i n s o f s i m p l e e p i t h e l i u m type cytokeratins. These f r a g m e n t s are p r o b a b l y r e l e a s e d d u r i n g n e c r o s i s a n d lysis of the c a r c i n o m a cells. Thus, TPA s h o u l d be r e g a r d e d as a b r o a d s p e c t r u m epithelial t u m o r m a r k e r a n d n o t as a specific molecular m a r k e r for epithelial n e o p l a s m s . Intracellular

tumor markers

I n t e r m e d i a t e filaments (IF) are a group o f i n t r a c e l l u l a r proteins w h i c h form t h e c y t o s k e l e t a l n e t w o r k . They are 8-I 0 n m in d i a m e t e r a n d c o n s i s t of a b o u t 5-6 c o n s t i t u e n t p r o t e i n s w h i c h are e x p r e s s e d in a h i g h l y t i s s u e specific m a n n e r (57). D u r i n g m a l i g n a n t t r a n s f o r m a t i o n their e x p r e s s i o n r e m a i n s t i s s u e specific a l t h o u g h there m a y be noticeable a l t e r a t i o n s in t h e i r p a t t e r n o f e x p r e s s i o n w h e n c o m p a r e d to the n o r m a l t i s s u e (3). This p r o p e r t y of IF h a s b e e n u s e d to differentiate t h e origin of c a r c i n o m a s (223). Below (in Table 2) are d e s c r i b e d v a r i o u s i n t r a c e l l u l a r p r o t e i n s a n d the t i s s u e for w h i c h t h e y are c h a r a c t e r i s t i c a n d c a n be u s e d as m a r k e r s Table 2 Constitutents

of IF

Cytokeratins Desmin Vimentin Neurofilaments and nestin Glial fibrillary acidic p r o t e i n Keratins

as tumor

Specificity T u m o r s derived T u m o r s derived T u m o r s derived T u m o r s derived Tumors derived

from from from from from

epithelial cells m u s c l e cells m e s e n c h y m a l cells n e u r o n a l cells a s t r o c y t e s a n d glial cells

markers

All t y p e o f epithelial cells c o n t a i n 30-85% o f k e r a t i n s as t h e m a j o r c y t o s k e l e t a l protein. This h a s led to exploring the possible u s e of k e r a t i n s a n d its c o n s t i t u e n t polypeptides as m a r k e r s for epithelioid m a l i g n a n c i e s (3). L i t e r a t u r e s u r v e y reveals t h a t k e r a t i n h a s been u s e d effectively as a m a r k e r for epithelial t u m o r s (for r e c e n t review; see Ref. 3), especially t h o s e of stratified a n d s q u a m o u s cell origin. For e x a m p l e l u n g c a r c i n o m a (37, 58-60), b r e a s t c a r c i n o m a s (61-63), u r i n a r y b l a d d e r c a r c i n o m a s (64), t h y m o m a s (65) a n d cervical c a r c i n o m a s (66). Since the g a s t r o i n t e s t i n a l (GI) t r a c t h n i n g is of epithelial origin, k e r a t i n serves as a u s e f u l m a r k e r for GI t u m o r s (48,67). Right f r o m t h e b u c c a l cavity to t h e r e c t u m , so also p a n c r e a s a n d gall bladder are covered by epithelial lining w h i c h e n a b l e s t h e special m e n t i o n of k e r a t i n as a m a r k e r in t h e s e cases. Oral c a n c e r s are m o s t l y (90%) of s q u a m o u s epithelial origin arid h e n c e k e r a t i n s are the b e s t possible histological as well as b i o c h e m i c a l m a r k e r s for t h e s e t u m o r s (68,69). O e s o p h a g e a l c a r c i n o m a s are also of epithelial origin a n d m a n y w o r k e r s have u s e d k e r a t i n to d i s t i n g u i s h t h e m (70. K e r a t i n h a s also b e e n widely u s e d as a m a r k e r in prostatic t u m o r s (71, 72). S v a n h o l m et. al. (73) have u s e d k e r a t i n to differentiate b e t w e e n prostatic h y p e r p l a s i a (a b e n i g n disorder) from prostatic a d e n o c a r c i n o m a .

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I n t r a c e l l u l a r P rot ei ns as T u m o r M a r k e r s

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We have u s e d k e r a t i n p o l y p e p t i d e s as m a r k e r s for g a s t r o i n t e s t i n a l c a r c i n o m a s a n d f o u n d that in all th e c a s e s ( b a r r i n g s q u a m o u s cell c a r c i n o m a s of t h e o e s o p h a g u s ) t h e e x p r e s s i o n o f keratin in t h e m a l i g n a n t t i s s u e d e c r e a s e s w h e n c o m p a r e d to n o r m a l t i ssue. We h a v e f o u n d t h a t normal c o l o r e c t a l e p i t h e l i u m e x p r e s s e s two k e r a t i n p o l y p e p t i d e s w h e r e a s t h e m a l i g n a n t l y tr an s f o r med cells e x p r e s s o n l y a single pol ypept i de b a n d (3]. Similarly, t h e n o r m a l g a s t r i c epithelium e x p r e s e s f o u r k e r a t i n p o l y p e p t i d e s w h e r e a s t h e m a l i g n a n t t i s s u e e x p r e s s e s t w o b a n d s . The a d e n o c a r c i n o m a s of t h e o e s o p h g u s s h o w a m a r k e d r e d u c t i o n in t h e e x p r e s s i o n of k e r a t i n polypeptides w h e n c o m p a r e d w i t h n o r m a l o e s o p h a g e a l e p i t h e l i u m w h i c h e x p r e s s e s e i g h t k e r a t i n polypeptides. We h a v e c o n c l u d e d in o u r s t u d i e s t h a t in t h e c a s e of k e r a t i n s , t he a b s e n c e o f a p a r t i c u l a r keratin b a n d c a n be u s e d as a m a r k e r in epithelioid g a s t r o i n t e s t i n a l m a l i g n a n c i e s . T hi s is in t o t a l contrast to t h e p a t t e r n o b s e r v e d in o t h e r t u m o r m a r k e r s so far. S e r u m t u m o r m a r k e r s s h o w significantly h i g h levels in c a n c e r o u s c o n d i t i o n s , w h e r e a s m a l i g n a n t t r a n s f o r m a t i o n o f e p i t h e l i a l cells c a u s e s a d e c r e a s e d e x p r e s s i o n o f k e r a t i n by a m e c h a n i s m y e t u n k n o w n . In a d d i t i o n to k e r a t i n s , o t h e r c y t o s k e l e t a l p r o t e i n s (21-23), o n c o g e n e r e g u l a t o r y e n z y m e s , enzymes involved i n p o s t - t r a n s l a t i o n a l m o d i f i c a t i o n of p r o t e i n s (24-27) a n d r e c e p t o r s c a n also serve as t u m o r m a r k e r s . B u t ver y little efforts have b e e n m a d e in this d i r e c t i o n to u s e t h e s e s u b s t a n c e s in d e t e c t i o n o f c a n c e r s in h u m a n s in clinical b i o c h e m i s t r y l a b o r a t o r i e s . N e v e r t h e l e s s , efforts ar e b e i n g m a d e to simplify t he t e c h n i q u e s for t h e i r d e t e c t i o n so t h e y c a n be a d o p t e d in clinical b i o c h e m i s t r y l a b o r a t o r i e s .

Conclusion With th e d e v e l o p m e n t of n e w a n d sensitive t e c h n i q u e s for d e t e c t i o n o f v e r y m i n u t e q u a n t i t i e s of b i o m o l e c u l e s n o w it is p o s s i b l e to identify t h e c h a n g e s in t h e levels o f g e n e r e g u l a t o r y e n z y m e s a n d o t h e r s u b s t a n c e s . Silver s t a i n i n g in SDS-PAGE ( 14), Radio r e c e p t o r [RRA] a n d Radi o i m m u n o a s s a y s [RIAl (75) e n z y m e l i nke d i u m m u n o a s s a y s [ELISA] (76), W e s t e r n ; N o r t h e r n a n d S o u t h e r n blotting t e c h n i q u e s (77,78) a m o n g o t h e r s c a n d e t e c t u p t o p i c o g r a m q u a n t i t i e s . C e l l u l a r p r o t e i n s s u c h as c y t o s k e l e t a l p r o t e i n s , m e m b r a n e b o u n d p r o t e i n s (37), c h r o m a t i n a s s o c i a t e d p r o t e i n s a n d gene r e g u l a t o r y e n z y m e s w h i c h a r e n o t s o l ubl e in o r d i n a r y a q u e o u s b u f f e r s a n d a r e n o n - s e c r e t o r y in n a t u r e c a n n o w be d e t e c t e d in n e e d l e biopsies by t he above m e n t i o n e d t e c h n i q u e s . S t e r o i d h o r m o n e r e c e p t o r a s s a y s a r e r o u t i n e l y d o n e in m a n y clinical b i o c h e m i s t r y l a b o r a t o r i e s i n o r d e r to d ecid e w h e t h e r t h e t u m o r f r o m b r e a s t , cervix or u t e r u s are h o r m o n e d e p e n d e n t o r not . T h e r e m a y be e i t h e r a n u p r e g u l a t i o n or d o w n r e g u l a t i o n of i n t r a c e U u l a r p r o t e i n s d u r i n g m a l i g n a n t t r a n s f o r m a t i o n d e p e n d i n g o n t h e s t i m u l u s given a n d t h e t a r g e t t i s s u e involved (3). So me p r o t e i n s w h i c h a r e s y n t h e s i z e d in t u m o r cells a n d s e c r e t e d in t h e s e r u m a r e u s e d for d e t e c t i o n a n d m o n i t o r i n g t h e t u m o r activity. T he o t h e r p r o t e i n s w h i c h a r e n o t s e c r e t e d c a n a lso be u s e d as t u m o r m a r k e r s as d e s c r i b e d in this review. I n t r a c e l l u l a r t u m o r m a r k e r s h a v e a n a d v a n t a g e over c o n v e n t i o n a l t u m o r m a r k e r s in t h a t t h e y c a n give v a l u a b l e i n f o r m a t i o n a b o u t t h e origin a n d d e g r e e o f d i f f e r e n t i a t i o n o f t u m o r s . T h e r e are v a r i o u s f a c t o r s w h i c h r e g u l a t e t h e e x p r e s s i o n o f i n t r a c e l l u l a r p r o t e i n s , for example, d o w n r e g u l a t i o n o f k e r a t i n p o l y p e p t i d e s is s e e n in GI t u m o r s . T he m e c h a n i s m o f this u p or d o w n r e g u l a t i o n is, however, n o t k n o w n yet. More w o r k on gene r e g u l a t o r s will give b e t t e r i ns i ght for c a n c e r d e t e c t i o n a n d m a n a g e m e n t .

86

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