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CD44 glycoproteins in colorectal cancer; expression, function and prognostic
value
Wielenga, V.J.M.
Publication date 1999
Link to publication
Citation for published version (APA):
Wielenga, V. J. M. (1999). CD44 glycoproteins in colorectal cancer; expression, function and prognostic value.
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Chapter 8
CD44 GLYCOPROTEINS IN COLORECTAL
CANCER; EXPRESSION, FUNCTION AND
PROGNOSTIC VALUE.
Vera J.M. Wielenga, Ronald van der Neut, G.Johan A. Offerhaus and Steven T. Pals
I. Introduction
II. Structure and function of CD44 A. The structure of CD44
B. CD44 glycoproteins: receptors for ECM components
C. CD44 isoforms decorated with heparan sulfate bind and present growth factors.
III. CD44 in tumor progression and metastasis
A. Expression and regulation of CD44 in colorectal cancer B. CD44 as a prognosticator in colorectal cancer
IV. Conclusions References
I. INTRODUCTION
Colorectal cancer is a common disease in the western world and represents the second leading cause of cancer-related death (Coleman et al., 1993; American Cancer Society, 1994). It evolves through a series of morphologically recognizable stages known as the adenoma carcinoma sequence (Muto et al, 1975). Recent advances in molecular genetics have greatly increased our understanding of the development of colorectal cancer (Kinzler et al., 1996; Korinek et al., 1997; Morin et al., 1997; Liu et al., 1996; Yingling étal, 1996). Tumor progression in the colorectum is characterized by a stepwise accumulation of specific molecular genetic alterations, ultimately resulting in invasive and metastatic cancer. Most of the molecules that have thus far been implicated in this neoplastic process either cause genetic instability or act on regulation of the cell cycle, thereby resulting in a disturbed homeostasis between cell proliferation and apoptosis. The main cause of cancer related death, however, is not growth of the primary tumor, but the formation of metastases in distant organs. Although relatively little is known about the molecular mechanisms underlying this complicated process, a large body of studies indicate an important role of CD44 (reviewed in: Lesley et al, 1993; Naorefa/., 1997).
CD44 was originally described as a homing receptor on lymphocytes, mediating lymphocyte interactions with high endothelial venules (HEV)
(Jalkanen et al, 1986, 1987). Metastasizing tumor cells and recirculating (activated) lymphocytes share several properties including motility and invasive behavior involving reversible adhesive contacts, accumulation and expansion in draining lymph nodes, release into the circulation, and adhesion to vascular endothelium and extravasation. This analogy between lymphocyte recirculation and tumor dissemination prompted the hypothesis that malignant cells might use molecules like CD44 for metastasis formation (Herrlich et al., 1993). Support for this hypothesis comes from experimental studies in laboratory animals showing a causal role of specific CD44 isoforms in metastasis formation, as well as from clinical studies documenting deregulated CD44 expression in human cancer (Lesley et al., 1993; Naor et al, 1997). On the other hand, contradictory reports concerning both the biological role of CD44 in tumorigenesisand its clinical usefulness as a prognosticatorhave been published. In this paper, we address these contradictions by summarizing and discussing the current literature on the expression, regulation, and prognostic value of CD44 in colorectal cancer. Furthermore, we present a model for CD44 function in colorectal tumorigenesis.
II. STRUCTURE AND FUNCTION OF CD44
A. The structure ofCD44
CD44 is a family of type I transmembrane glycoproteins that are widely expressed on a variety of cells including cells of epithelial, mesenchymal, and hematopoietic origin. All CD44 family members are encoded by a single gene on chromosome 1 lpl3 that consists of 19 exons (Fig.l) (Stamenkovic et al, 1989; Screaton et al, 1992). They share the N-terminal cartilage link protein homology domain encoded by exon 1-5, which binds hyaluronic acid (HA) (Stamenkovic et al, 1989; Aruffo et al, 1990; Peach et al, 1993). However, as a result of extensive alternative splicing of exons 6-14 (also referred to as exons v2-vl 0), the extracellular membrane proximal domain of CD44 is highly variable (Günthert et al, 1991; Dougherty et al, 1991; Screaton et al, 1992; Tölg et al, 1993). Additional diversity of CD44 results from post-translational modifications with jV-and 0-linked sugars and glycosaminoglycan(GAG) side chains (Stamenkovic et al, 1989; Brown et al, 1991; Faassen et al, 1992;
Cartilage link protein homology domain He \ . Growth factors: HGF/SF FGF Plasma mantrane
yy&iyyyyyyyöy:yöyi
Figure 1. Schematical representation of the CD44 gene and its encoded proteins. The
extracellular domain and cytoplasmic tail of CD44 isoforms vary in size as the result of alternative splicing. The alternative spliced exons are indicated by open boxes. The human vl exon contains a stop codon. In the model of the potein, all putative glycosylation sites are indicated: <9-glycosylation(open circles); 7V*-glycosylation(closed circles); chondroitin sulfate (open squares); heparan sulfate chain (rod). As indicated, the heparan sulfate binding site in exon v3 has the ability to bind growth factors. In addition, the HA-binding sites (double lines) ; the disulfide bonds (S-S); the ankyrin binding site (...); the ezrin binding sites (---); the phosphorylation sites (P); and the putative interaction sites for SRC-family kinases, are indicated.
Jalkanen and Jalkanen 1992; Jackson et al, 1995a). The expression of CD44 isoforms is tissue specific. For example, the shortest isoform of CD44 (CD44s), which lacks all variable exons, is the most common form on hematopoietic cells, whereas larger CD44 splice variants dominate on several normal epithelia. These variant isoforms are also expressed on neoplastic epithelia and on activated lymphocytes and malignant lymphomas (Günthert et al, 1991; Dougherty et al, 1991; Screatone/a/., 1992; Heidere? al, 1993, 1995; Fox et
al, 1994, Arch et al, 1992; Koopman et al, 1993; Stauder et al, 1995). B. CD44 glycoproteins: receptors for ECM components.
CD44 has been implicated in lymphocyte homing and activation, hematopoiesis, and tumor progression and metastasis (Lesley et al, 1993 ; Naor
et al, 1997). It is believed to function in these processes as a cell adhesion
receptor, linking the cell and the cytoskeleton to extracellular matrix (ECM) molecules.The CD44 cytoplasmic tail associates with the actin cytoskeleton via ankyrin and proteins of the ERM-family. These cytoskeletal interactions may regulate hyaluronic acid (HA) binding and CD44-dependent cell motility as well as inside-out signaling events (Lesley ef al, 1993; Kalomiris et al, 1988; Tsukitae/a/., 1994; Legg and Isacke 1998; Sheikh et al, 1998). Importantly, a number of studies have indicated that CD44 can function as a signal-transducing receptor. Engagement of CD44 costimulates antigen-specific lymphocyte activation and proliferation and leads to activation of integrins on the lymphocyte cell-surface (Haynes et al 1989; Shimizu et al 1989; Koopman et al. 1990). CD44 can associate with the Src family member p56lck
and triggering of CD44 results in an increased p56lck activity and in
phosphorylation of a number of intracellular proteins including ZAP-70 (Taher
etal, 1996, 1999).
CD44 is a maj or receptor for hyaluronate, a GAG that is abundant in the ECM of mesenchymal tissues and that plays a regulating role in cell migration during inflammation, wound healing, and development (Aruffo et al, 1990; Lesley et al, 1993; Knudson et al, 1993). The binding site for HA is located on the N-terminal part of CD44, which is present in all isoforms. However, HA-binding capacity is not a constant feature of CD44, but is subject to complex regulation by mechanisms involving both alternative splicing,
modulation of cytoskeletal interaction, and posttranslational modification of CD44 (Van der Voort et al, 1995; Bennett et al, 1995a; Katoh et al, 1995; Seikh et al, 1998). By altering cellular interactions with HA, CD44 might facilitate tumor metastasis at two distinct levels. First, it might promote cell migration through the ECM. Second, it might facilitate rolling of tumor cells on HA expressed on the surface of vascular endothelium, thereby promoting extravasation(DeGrendelee/ al, 1996; 1997). Indeed, Bartolazzi et al, (1994) reported that HA binding is essential for the metastasis promoting effect of CD44s in melanoma cell lines. In pancreatic carcinoma cell lines, however, Sleeman et al, (1996) found no relation between HA-binding capacity and metastatic potential, indicating that in this tumor type other properties of CD44 promote metastasis. Additional molecules that have been reported to interact with CD44 are collagen IV, fibronectin, serglycin, and osteopontin; the biological significance of these interactions needs further study (Carter and Wayner, 1988; Jalkanene/ al, 1992; Toyamae/1 al, 1995; Weber et al, 1996).
As will be discussed below, the recently discovered novel function of CD44,
i.e., binding and presentation of growth factors, might shed new light on the
mechanism of tumor formation.
C. CD44 isoforms decorated with heparan sulfate bind and present growth factors.
CD44 can be modified by both chondroitin- and heparan-sulfate side chains and is thus a "facultative" cell-surface proteoglycan (Brown et al, 1991 ; Faassen et al, 1992; Jalkanen et al, 1988; Jackson et al, 1995a). Heparan sulfate (HS) modifications are associated with v3 containing CD44 isoforms (Jackson et al., 1995a), which possess a consensus motif SGSG for HS addition (Bourdon et al, 1987). HS-proteoglycans are involved in regulation of cell growth and motility (Kjellén and Lindahl, 1991; Ruoshlati and Yamaguchi, 1991 ; Schlessinger et al., 1995). These molecules bind growth factors via their HS side-chains and target these factors to their high affinity signal transducing receptors. This process has been particularly well explored for fibroblast growth factor (FGF)-2. Binding of FGF-2 to the low affinity proteoglycan receptor on the cell-surface allows more frequent encounters with the high affinity receptor. Furthermore, formation of a multivalent FGF-proteoglycan
complex promotes dimerization of the high affinity receptors essential for signaling (Yayonef al, 1991 ; Ruoslahti et al., 1991; Schlessingere/a/., 1995). Importantly, structural modifications of HS side-chains determine their specificity for a given heparin-binding growth factor, creating a mechanism for cell or tissue selective growth factor binding (David, 1993; Lindahl et al, 1994; Lyon et al, 1994; Tanaka et al, 1998).
Tanaka and colleagues (1993) have shown that heparan sulfate proteoglycan forms of CD44 (CD44-HS) can present the chemokine MIP-lß to T lymphocytes, resulting in integrin activation. Subsequently, studies by Bennett and colleagues (1995b) demonstrated binding of FGF-2. During embryogenesis, presentation of this growth factor by CD44-HS expressed on the apical epidermal ridge appears to be crucial for limb bud formation (Sherman et al, 1998). Recent studies from our own laboratory have indicated that CD44-HS can also bind Hepatocyte Growth Factor/Scatter Factor (HGF/SF). Presentation of HGF/SF by CD44-HS, strongly promotes signaling through its high affinity receptor, the receptor tyrosine kinase c-Met, leading to enhanced activation of the ERK1/2 MAP kinases as well as to hyperphosphorylationof several other cytoplasmic proteins (Van der Voort et
al, 1999; Taher et al, 1999). This observation provides an important novel
functional link between CD44 and metastasis formation: HGF/SF is a member of the plasminogen-related growth factor family that induces growth, and motility of target epithelial cells, endothelial cells, myoblasts, and lymphocytes (Stoker et al, 1987;Bottaroera/., 1991; Bussolino etal, 1992; Tajimae/a/., 1992; Weidneretal, 1993; Donated al, \994;B\adt et al, 1995;Boros et al, 1995; Brinkmann et al, 1995; Van der Voort et al, 1997). Apart from these physiological functions, the c-Met - HGF/SF pathway promotes invasion and metastasis. Stimulation of c-Met by HGF/SF induces epithelial cells to invade collagen matrices in vitro, whereas cotransfection of c-met and HGF/SF induces an invasive and metastatic phenotype in NIH-3T3 cells (Weidner et al, 1990; Rongetal., 1992; Giordano et al., 1993; Rongea/., 1994). In HGF/SF transgenic mice, tumorigenesis was observed in many different tissues including mammary glands, skeletal muscles, and melanocytes (Takayama et
HGF/SF Cytoplasm D SH homologue GSK3B \ mutant APC
¥
ß -catenin + TCF-4 \ Motility f t Prolifération*! Apoptosis^ CD44 f f V . deregulated splicing 7Figure 2. Regulation and function of CD44 in colorectal tumorigenesis. Due to an APC mutation, the Wnt pathway is constitutively activated in colorectal cancer and
uncontrolled amounts of ß-catenin will complex with Tcf-4 and enter the nucleus. Transcription of target genes, including CD44 will be promoted, resulting in an enhanced level of CD44 protein expression on the cell membrane. The tumor promoting effect of CD44 can be due to either hyaluronate binding resulting in enhanced cell motility or in modulation of signaling involved in regulation of motility and proliferation. Signaling can be mediated via the cytoplasmic tail of CD44 or by presentation of heparin binding growth factors, such as HGF/SF.
mutations have recently been indentified (Schmidt et al, 1997). NIH-3T3 expressing these mutant c-Met molecules are transformed in vitro and tumorigenic in vivo (Jeffers et al, 1998). We hypothesize that tumor cells, by overexpressingCD44-HS, acquire an increased sensitivity to HGF/SF, leading to a growth advantage and to an invasive and metastastic phenotype similar to that observed in c-Met mutants (Fig.2). This hypothesis is supported by the fact that CD44-HS is overexpressed in conjunction with c-Met in a variety of
tumors including colorectal cancer (Liu et al, 1992; Yamashita et al, 1994; DiRenzo et al, 1995; Tuck et al, 1996; Wielengae/ al., in preparation). Hence, functional collaboration between CD44-HS and the c-Met-HGF/SF pathway presumably is an important factor in tumor growth and metastasis.
III. CD44 IN TUMOR PROGRESSION AND METASTASIS
The initial observations relating CD44 expression to tumor dissemination were made in human non-Hodgkin's lymphomas by us and the group of Jalkanen (Pals et al, 1989; Horst et al, 1990; Koopman et al, 1993; Jalkanen et al, 1990; Jalkanen et al, 1991). In these studies, expression of CD44 on human lymphomas was found to be linked to tumor dissemination and to unfavorable prognosis. Sy and colleagues (1991) demonstrated that CD44s enhances growth and metastasis of human lymphoma cells in nude mice. The observation by Günthert et al, ( 1991 ) that a CD44 variant containing exon v6 could confer metastatic potential to a rat pancreas carcinoma cell line provoked numerous studies on CD44 variants in a wide variety of human tumors. In gastrointestinal cancer (Matsumurae/ al, 1992; Heider et al, 1993;
Tanabeetal, 1993; Wielenga e/a/., 1993; Finn et al, 1994; Kim et al, 1994; Mulderetal, 1994;Orzechowski^a/., 1995; Rodriguezes/., 1995; Imazeki et al, 1996; Yamaguchi et al, 1996), breast cancer (Matsumura et al, 1992;
Kaufmann et al, 1995), non-Hodgkin's lymphomas (Koopman et al, 1993; Stauder et al, 1995), cervical (Dali et al, 1994) and bladder cancer (Cooper et
al, 1995) and central nervous system malignancies (Kaaijk et al, 1995)
increased levels of CD44 or altered splicing patterns have been found. Recently it was shown that expression of antisense CD44v6 mRNA in the colorectal tumor cell line HT-29 suppresses growth and metatatic behavior in nude mice (Reeder et al, 1988). In the next paragraphs, we will discuss the currently available data on CD44 expression in colorectal cancer.
A. Expression and regulation ofCD44 in colorectal cancer
Colorectal cancer serves as a paradigm of multistep tumorigenesis in epithelial cancer. It evolves through a series of morphologically well defined stages accompanied by progressive accumulation of genetic changes involving
components of the Wnt-signaling cascade (APC or ß-catenin), the ras oncogene family, the p53 and the TGFß II receptor tumor suppressor pathways (Kinzler and Vogelstein, 1996).This prompted us and others to use colorectal cancer as a model to study CD44 expression in relation to tumor progression. These studies have provided compelling evidence for grossly enhanced and deregulated expression of CD44 during colorectal cancer development (summarized in Table 1 and 2).
In the normal colorectal mucosa, CD44 protein is expressed at low levels and is confined to the base of the crypts. A similar distribution pattern was found for CD44s and for variant exons (Abbasi et al, 1993; Heider et al, 1993; Wielenga e/a/., 1993; Fox étal, 1994; Heider ef a/., 1995; Jackson et
al, 1995b; Gorham et al, 1996; Gotley et al, 1996; Kawahara et al, 1996;
Woodman et al, 1996; Yamaguchi et al, 1996; Coppola et al, 1998; Givechian et al, 1998; Ropponen et al, 1998; Wielenga et al, 1998). In colorectal tumors, expression of CD44 protein, including domains encoded by variant exons, is generally strongly enhanced in comparison to normal mucosa (Fig.3), although there is marked inter- and intra- tumor heterogeneity. The enhanced CD44 protein expression reflects (de)regulationat the transcriptional level, as more and larger transcripts were consistently amplified from tumor tissue (Table 2). The relative increase in mRNA containing variant exon sequences over CD44s mRNA, was interpreted to reflect infidelity of the splicing machinery within the tumor cells. A recent study, however, has challenged this interpretation: By selective RT-PCR of enriched colon crypt cells the same set of isoforms was found in the normal and in the neoplastic colorectal epithelium (Givechian et al, 1998). Further studies are needed to clarify this issue.
The major upregulation of CD44 occurs at the transition from normal mucosa to adenoma, indicating that deregulation of CD44 represents an early event in the adenoma-carcinoma sequence (Abbasi et al, 1993; Heider et al,
norm ;il
/•
J-J,:
Figure 3. Expression of CD44 during colorectal tumorigenesis. Whereas CD44
expression in normal colorectal epithelium is low and confined to the base of the crypts, it is enhanced in adenomas and in carcinomas. Stainings for CD44v6 are shown
al., 1996; Kinzier et al., 1996; Korinek et al, 1997; Morin et al, 1997; Coppola
et al, 1998). This suggests a causal relation for mutations involving
components of the Wnt-signaling cascade, as these play a key role in the initial neoplastic transformation of colon epithelium (Kinzler and Vogelstein, 1996; Korinek et al, 1997; Morin et al, 1997). A recent study from our laboratory' analyzing CD44 expression in the intestinal mucosa of mice and humans with genetic defects in Ape or Tcf-4 indeed strongly supports a regulatory role of Wnt-pathway in CD44 expression (Wielenga et al 1999). We observed enhanced CD44 expression in tumors arising in the intestinal mucosa of humans with a germline APC mutation, i.e., familial adenomatous polyposis patients, as well as in Ape mutant mice. Importantly, this CD44 overexpression was not only present in adenomas and invasive carcinomas, but already in aberrant crypt foci with dysplasia, i.e., in the earliest detectable neoplastic lesions. These lesions show loss of the wild-type copy of the APC gene but
neither ras norp53 mutations. In sharp contrast, Tcf-4 mutant mice, which have a disrupted Wnt-signaling pathway, show a complete absence of CD44 in the intestinal mucosa. Taken together, these results indicate that CD44 is upregulated in an early phase of colorectal tumorigenesis, as a direct or indirect result of a constitutive activation of the Wnt-pathway (Fig.2) ( Wielenga et al.,
1999).
Transfection of mutant APC cells with wild type APC leads to apoptosis (Morin et al, 1996). Interestingly, COX2 inhibition by NSAID's such as Sulindac has a similar effect, and is accompanied by redristribution of ß-catenin from the nucleus to the cytoplasm, suggesting parallelism between APC function and COX2 inhibition (Morin et al., 1996; Beazer-Barclay et al., 1996; Chan et ai, 1998). Since CD44 expression was also reported to have a negative effect on apoptosis (Koopman et al., 1994; Ayroldi et al, 1995; Günthert et al, 1996; Yu et al, 1997), it could be one of the molecules, together with COX2, via which a constitutive active Wnt-pathway results in a decrease in apoptosis.
B. CD44 as a prognosticator in colorectal cancer
As CD44 splice variants containing v6 were shown to confer metastatic potential to rat carcinoma cell lines (Günthert et al, 1991), overexpression of CD44 variants on colorectal carcinomas might also increase metastatic propensity, leading to disseminated disease and tumor-related death. To address this hypothesis, a number of studies have assessed the relation between CD44 expression on the primary tumor at surgery and tumor dissemination (Dukes' stage) and prognosis. Although a positive correlation between CD44 expression and Dukes' stage was found in only about half of the studies (Table 1 and 2), a strong correlation between CD44 expression and tumor related death was observed in all major studies that have thus far been published (Table 1).
In a study group of 68 patients with a complete long-term follow-up (6.5-9.5 years), we observed a strong correlation between CD44v6 expression and tumor-related death. In patients who had undergone an apparently radical resection of their primary tumor, the level of CD44v6 expression had prognostic value independent of Dukes' stage, tumor grade, and tumor localization (Mulder et al 1994; Wielenga et al. 1998). By using a panel of
three anti-CD44v6 antibodies for detection, recognizing the same epitope but with different affinity, an increased prognostic significance was obtained (Wielenga et al. 1998).
The results of the above study were confirmed by three large immunohistochemical studies by Yamaguchi et al. (1996), Ropponen et al. (1998), and Bhatavdekar et al. (1998). In the study by Yamaguchi et al, (1996), CD44v8-10 expression instead of CD44v6, was assessed. The study group consisted of 215 patients with a median follow-up of 10 years. In the study by Ropponen, CD44s, CD44v3, and CD44v6, were assessed in 194 patients with a median follow-up of 14 years. Bhatavdekar et al demonstrate a significant correlation of CD44s with survival in 98 patients with a median follow-up of 60 month. In all three studies, expression of CD44 had independent prognostic value in patients after radical surgery. This relation was similar for CD44s, CD44v8-10, CD44v3, and CD44v6.
In contrast, Coppola er al (1998) did not observe a correlation between CD44 expression and survival in colorectal cancer patients. This study, however, suffers from a number of major drawbacks. Most importantly, the authors used a single low affinity mAb (VFF7) on formalin-fixed material to detect CD44v6. Strong CD44v6 expression was detected in only 5% of the carcinomas, and was often localized in the cytoplasm instead of on the cell membrane. Added up to a relatively small patient group (n=34) and short follow-up (mean 17.6 month) this presumably explains the discrepant results. The use of the same low-affinity antibody can explain the negative results of Koretz et al. (1995) (Pals et al 1995).
In conclusion, CD44 expression, assessed with mAbs against either CD44v3, v6, or v8-10, is a strong independent prognosticator in patients with .colorectal cancer. CD44 expression reflects propensity for metastasis after apparently curative surgery and may be used to select patients that might benefit from adjuvant therapy.
IV. CONCLUSIONS
Studies from several laboratories have explored the expression and prognostic value of CD44 expression in colorectal cancer. Despite
discrepancies, which can largely be attributed to technical differences, the following important conclusions can be drawn. First, CD44 mRNA and protein are upregulated in colorectal cancer. In the adenoma-carcinoma sequence the major increase of CD44 occurs at the transition from normal mucosa to adenoma, i.e., in dysplastic aberrant crypt foci. Hence, it is closely associated with loss of APC/ß-catenin tumor suppressor function, and presumably results from constitutive activation of the Wnt-signaling pathway. Growth factor binding, as well as apoptosis inhibition by CD44, likely are instrumental in the growth advantage of CD44-bearing tumor cells. Second, several independent studies indicate that CD44 expression is an important independent prognosticatorin colorectal cancer patients. In patients who had an apparently radical resection CD44v6 (as well as v3, v8-10, and CD44s) expression predicts tumor related death. CD44 expression reflects propensity for metastasis after apparently curative surgery and may be used to select patients that might benefit from adjuvant therapy.
Acknowledgments
We thank Dr. Frank van den Berg for helpfull discussions. This work was supported by grants from the Praeventiefonds (project nr. 28-2575), and the Dutch Cancer Society (project nr. UVA 98-1712 and RUL 94-817).
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