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PubMed2005

Prognostic evaluation of CD44 expression in correlation with bcl-2 and p53 in colorectal cancer.

To investigate the expression of CD44 in colorectal cancer and examine its association with clinicopathological features, bcl-2, p53 and long-term outcome, paraffin-embedded tumour specimens from 61 patients with Dukes stage B (AJCC/UICC stage I) and 39 patients with Dukes stage C (AJCC/UICC stage III) colorectal adenocarcinoma were assessed by immunohistochemistry. The expression of CD44, bcl-2 and p53 were correlated with 5-year follow-up. Low CD44 expression was present in 30%, moderate in 30% and extensive in 40% of cases. It was not related to patient sex and age but was related to tumour differentiation, stage and tumour site. No association was demonstrated between CD44 and bcl-2. However, there was significant evidence of an association between CD44 and p53 in 66 cases in which p53 was previously assessed. There was a trend towards increased survival in patients whose tumours expressed lower levels of CD44 protein. When entered into multivariate analysis model, which also included bcl-2 and p53, CD44 staining emerged as an indicator of poor prognosis in colorectal cancer patients.

Adenocarcinoma↗
PubMedDate not supplied

The significance of CD44 expression in gastrointestinal neuroendocrine tumors.

BACKGROUND/AIMS: Expression of CD44 and its isoforms has been demonstrated to be a prognostic marker in many neoplasms. Gastrointestinal neuroendocrine tumor is a slow-growing neoplasm, whose behavior is determined by site of occurrence, size or specific histologic growth pattern. In this study, the feasibility of using CD44 as a prognostic marker in gastrointestinal neuroendocrine tumor is evaluated. METHODOLOGY: Representative paraffin-embedded sections of gastrointestinal neuroendocrine tumor from 22 patients were studied by immunohistochemical staining using monoclonal antibodies against CD44, Ki-67, and p53 retrospectively. The correlation between these markers and clinical behavior of the tumors was analyzed. RESULTS: Positive expression of CD44 was observed in 15 cases (68%) of gastrointestinal neuroendocrine tumor. Expression of CD44 showed significant inverse correlation with lymph node status (P=0.049), distant metastasis (p<0.001) and mortality (p=0.002). Neither p53 nor Ki-67 correlated with lymph node status, distant metastasis and overall survival. Both lymph node status and distant metastasis showed strong correlation to survival after multivariate analysis. Patients with the tumor growing from the hindgut had better survival (p=0.024). The patients with stronger CD44 immunoreactivity (> or = 2+) tumors had significantly favorable survival (p=0.004) compared with those with weaker immunoreactivity (< or = 1+) tumors. CONCLUSIONS: Expression of CD44 in gastrointestinal neuroendocrine tumor inversely correlates with tumor metastasis, associates with a favorable outcome and may serve as one of the prognostic indicators.

Adult↗
PubMed1991

Isolation and characterization of human melanoma cell variants expressing high and low levels of CD44.

Variants of the human melanoma cell line LT5.1 were selected for high and low expression of the Mr 90,000 CD44 glycoprotein by using the Hermes-3 monoclonal antibody combined with fluorescence-activated cell sorting. Cells were single cell cloned and clones of CD44 high-expressing and CD44 low-expressing phenotype were isolated. The variants, which exhibited up to a 7-fold difference between high and low expression, have maintained a stable phenotype over a period of 3 months in tissue culture. Northern blot analysis of mRNA from the different clones showed correlation of levels of transcripts with fluorescence-activated cell sorting analysis data. Wound migration assays, utilizing the different clones, showed that the low-expressing clones manifested less motility than did cells showing high levels of CD44. Homotypic aggregation of cells was increased in those cells expressing high levels of CD44, and these variants were also better able to adhere to hyaluronate substrates. All of these activities were inhibited by the presence of anti-CD44 antibody. When injected i.v. into nu/nu BALB/c mice, the low-expressing clones gave significantly fewer lung nodules than the high-expressing clones, although the two variant types did not differ in their capacity to form s.c. tumors in similar mice. These results suggest that the CD44 molecule, possibly as a function of its activities as a hyaluronate receptor, may play a vital role in determining the fate of hematogenously disseminating melanoma cells.

Animals↗
PubMed1993

Elevation of intracellular cAMP in human T lymphocytes by an anti-CD44 mAb.

Regulation of lymphocyte responses to activation of the CD3/TCR complex by other cell surface proteins expressed on lymphocytes is a well established phenomenon. CD44 is an example of such a cell surface protein. Anti-CD44 mAb have been identified which either stimulate or inhibit lymphocyte function. Certain anti-CD44 mAb augment proliferation and IL-2 production by T cells stimulated through the CD2 or CD3/TCR pathways. An anti-CD44 mAb with opposing properties has also been identified. This mAb inhibits activation of human T cells by preventing the rise in [Ca2+]i stimulated by OKT3. The purpose of experiments reported here was to further characterize this phenomenon. The results show that the anti-CD44 mAb, 212.3, does not inhibit inositol phosphate turnover stimulated by OKT3 but does inhibit elevation of intracellular [Ca2+]i in these same cells. Addition of 212.3 to purified human T cells results in a rapid increase in intracellular levels of cAMP. Elevation of cAMP by 212.3 is time- and concentration-dependent. Activation of adenylate cyclase by forskolin also results in elevation of intracellular cAMP and inhibition of the increase in [Ca2+]i stimulated by OKT3. Taken together, these data suggest that CD44 may be positively coupled to adenylate cyclase and that activation of adenylate cyclase by the anti-CD44 mAb, 212.3, may mediate the inhibition of the OKT3-stimulated elevation of [Ca2+]i.

Animals↗
PubMed1994

Potential use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer.

Soluble CD44 is present in the serum of normal individuals (2.7 +/- 1.1 nM). The concentration of soluble CD44 in the serum is elevated in patients with advanced gastric (24.2 +/- 9.8 nM) or colon cancer (30.8 +/- 11 nM). Serum CD44 concentration correlated with tumor metastasis and tumor burden. Surgical resection of tumors resulted in decreases in serum CD44 levels. By Western blot analysis, monoclonal anti-CD44 antibody reacted with a major protein with molecular weight between 130,000 and 190,000. In addition, two proteins with molecular weights of 72,000 and 80,000 can also be identified. Therefore, different CD44 isoforms may be present in the serum of cancer patients. Serum CD44 concentrations may be an indicator of tumor burden and metastasis in patients with malignant diseases.

Adenocarcinoma↗
PubMed1994

Ligand binding specificity of alternatively spliced CD44 isoforms. Recognition and binding of hyaluronan by CD44R1.

CD44 species of widely differing molecular mass have been identified on various normal and/or transformed cells. Recent studies have demonstrated that much of this heterogeneity is produced as a result of the alternative splicing of a series of 10 exons present within the CD44 gene generating a large number of CD44 isoforms containing additional peptide sequences of varying length inserted into a single site within the extracellular domain of the molecule. At present, the effect of such insertions on the ligand binding specificity of CD44 remains unclear. CD44H, the major CD44 isoform expressed by most resting cell types, has been shown to function as a receptor for the glycosaminoglycan hyaluronan. In contrast, CD44E, the major isoform expressed by the colon carcinoma cell line HT29, which contains a 132-amino acid insert, is unable to recognize and bind this ligand. In the present study we demonstrate that CD44R1, an isoform isolated from the myelomonocytic cell line KG1a, that differs from CD44E by just 3 amino acid substitutions, is fully capable of mediating the attachment of transfected COS7 cells to hyaluronan-coated plastic. In order to confirm that such binding was directly mediated by the introduced CD44 species, chimeric proteins containing the entire extracellular domain of CD44H or CD44R1 fused in-frame to human bone/liver/kidney alkaline phosphatase were prepared and tested for their ability to bind hyaluronan-coated plastic. Both fusion proteins bound equally well to hyaluronan and in each case their attachment could be readily inhibited by monoclonal antibodies directed against the hyaluronan-binding domain of CD44. These data indicate that the 132-amino acid insert present within the extracellular domain of CD44R1 does not interfere with the hyaluronan binding function of the molecule. Since CD44E contains an identically sized insert but is unable to bind hyaluronan, it is likely that mutation of one or more of the 3 amino acid residues that differ between CD44E and CD44R1 is responsible for the altered functional activity of this particular molecule.

Alternative Splicing↗
PubMed1994

Hyaluronate is costimulatory for human T cell effector functions and binds to CD44 on activated T cells.

Lymphohematopoiesis, cell matrix adhesion, homing of leukocytes, T cell activation, and tumor metastasis are mediated through the CD44 family of cell surface receptors. We have recently shown that anti-CD44 mAb trigger protein tyrosine kinase-dependent activation of T cell effector functions. Here, we show that hyaluronate (HA), a CD44 ligand, in conjunction with CD3/TCR-mediated stimuli, is costimulatory for human peripheral blood T cell proliferation, for IL-2 production by Th clones, and for release of trypsin-like esterase by cytolytic T cell clones. A human T cell line, HUT-78, was found to bind HA and on HA coating it was used as a target for cytolytic T cell clones. After anti-CD3 stimulation, CD3+/CD8+ clones acquire the ability of lysing HA-coated HUT-78 cells more efficiently than the same HA-uncoated targets. Resting peripheral blood T cells and T cell clones do not adhere to HA-coated plates. However, 24-h anti-CD3 mAb stimulation gives them the transient ability to bind HA. HA adhesion of activated T cells and T cell clones, as well as that of T cell lines, is blocked by one anti-CD44 mAb (J-173). Two other anti-CD44 mAbs induce a 10-fold increase in HA adhesiveness of anti-CD3-stimulated peripheral blood T cells. This impressive HA adhesiveness is also readily blocked by J-173 anti-CD44 mAb. These data indicate that 1) HA is costimulatory for human T cell effector functions in conjunction with CD3/TCR-mediated stimuli, 2) the capacity to bind HA is acquired by resting T cells and T cell clones after anti-CD3 stimulation, and 3) HA binding occurs via specific interaction with CD44 molecules expressed on activated T cells.

CD4-Positive T-Lymphocytes↗
PubMed1994

Surface protein expression and messenger RNA-splicing analysis of CD44 in uterine cervical cancer and normal cervical epithelium.

Variant CD44 has recently been shown to serve as a metastasis marker in human breast cancer. Certain variant epitopes on primary tumors predict poor survival probabilities for the patients. In this study, immunohistochemical analysis of 16 uterine cervical carcinomas showed strong expression of several CD44 variant epitopes in all samples. In normal cervical epithelia from 5 patients, expression of these epitopes was restricted to particular cell layers, with expression being strong in basal and spinal cells but absent in superficial cells. Fifteen of 16 cancer samples were stained strongly with an antibody which recognizes one particular CD44 epitope that is encoded by both variant exons v7 and v8. This epitope was not detectable in normal cervical epithelium. CD44-mRNA splicing analysis showed qualitative and quantitative differences between malignant and normal tissues with a much more complex splice pattern and high expression of a large CD44 isoform containing variant exons v3 to v10 (including the v7/v8 transition epitope) in about one-half of the cancer samples. Interestingly, patients with lymph node metastases were in this group only. These differences in CD44 epitope expression and mRNA splicing in cervical carcinoma reveal dynamic changes in CD44 expression during carcinogenesis. Such changes could provide metastatic cells with a selective advantage during the carcinogenic process. Furthermore, the v7/v8 epitope may be suitable for screening early stages of cervical cancer.

Adenocarcinoma↗
PubMed1995

CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor.

Isoforms of the transmembrane glycoprotein CD44, generated by alternative RNA splicing, have been correlated to tumor dissemination. For evaluation of the potential role of CD44 variant isoforms in non-Hodgkin's lymphoma (NHL), the presence of CD44 isoforms was analyzed in a large panel of reactive and neoplastic lymphoid tissues by immunohistochemical staining, as well as detection of CD44 variant RNAs by the reverse transcriptase-polymerase chain reaction. Whereas the CD44 standard or hematopoietic isoform (CD44s), devoid of the variant regions, was expressed in all leukocyte subpopulations, the variant isoforms (CD44v) showed a highly restricted pattern of expression, mainly observed in epithelial layers of lymphoid tissues and subpopulations of leukocytes after stimulation. In addition to a strong expression of CD44s, variant isoforms containing CD44-6v in combination with other variant exons were observed predominantly in aggressive lymphoma and were associated with a shorter overall survival of patients (n = 138; P < .0001). Moreover, multivariate analysis indicated CD44-6v as a new independent prognostic parameter in high grade NHL in comparison with the risk groups defined by the International NHL Lymphoma Prognostic Factors Project (N Engl J Med 329:987, 1993).

Adolescent↗
PubMed1995

Deregulated alternative splicing of CD44 messenger RNA transcripts in neoplastic and nonneoplastic lesions of the human thyroid.

CD44 is a polymorphic family of immunologically related cell surface proteoglycans and glycoproteins implicated in cell-cell and cell-matrix adhesion interactions, lymphocyte activation and homing, cell migration, and tumor metastasis. CD44 exists as a standard form and as multiple isoforms, each generated by alternative splicing of up to 10 variant exons (termed v1-v10) encoding parts of the extracellular domain. Using semiquantitative reverse transcriptase-PCR and Southern hybridization, alternative CD44 mRNA splicing was examined in 10 papillary thyroid carcinomas, 8 nodular goiters, 9 adenomas, 2 cases of thyroiditis, and 3 histologically normal thyroid controls. The amount of input cDNA for the CD44 PCRs was standardized against an internal control gene (glyceraldehyde phosphate dehydrogenase). Four papillary carcinomas showed significant overexpression of CD44 transcripts migrating between 750 and 1000 bp. These cases demonstrated reduced levels of the 482-bp standard isoform transcript. In six papillary cancers, we found a prominent v6-containing isoform at 750 bp that was present in only trace amounts in normal thyroid tissue. It is of interest that similar findings were seen in the majority of the goiters and adenomas but not in the cases of thyroiditis. These results show that deregulation of alternative CD44 splicing is a common feature of disordered thyroid follicular cell growth, both in neoplastic and nonneoplastic lesions. The data imply an important role for CD44, including CD44v6, in the pathogenesis of various thyroid lesions.

Adenocarcinoma, Papillary↗
PubMed1993

T cells expressing both L-selectin and CD44 molecules increase in number in peritoneal exudate cells and in vitro-stimulated spleen cells from mice immunized intraperitoneally with Listeria monocytogenes.

L-selectin, which was first reported as MEL-14 antigen in mice, is a type of animal lectin and expressed on lymphocytes, neutrophils and macrophages. L-selectin has been reported to be a homing receptor of lymphocytes to peripheral lymph nodes and to have an important role in initial adhesion of lymphocytes and neutrophils to endothelial cells activated by inflammatory cytokines. On the other hand, it has been reported that naive T cells express L-selectin while memory T cells and in vitro antigen-stimulated T cells lose its expression. If all memory T cells lack L-selectin, trafficking of memory T cells into inflammatory sites would be difficult. To know whether all memory T cells lack L-selectin expression, kinetics of expression of L-selectin was analysed on memory T-cell subsets, which are detected by expression of CD44, in mice after intraperitoneal immunization with a sublethal dose of viable Listeria monocytogenes. T cells expressing both L-selectin and CD44 were detected in splenocytes and peritoneal exudate cells (PEC) from untreated mice, though at low levels. L-selectin+ CD44+ T cells increased in PEC, which are known to be highly enriched in antigen-primed T cells, and reached maximum level on day 14 after immunization. Furthermore, we found increases not only of L-selectin- CD44+ but also of L-selectin+ CD44+ T cells by in vitro Listeria antigen stimulation of Listeria-immune spleen cells on day 14. These results showed that T cells expressing both L-selectin and CD44 increase after antigen stimulation in vivo and in vitro. The L-selectin+ CD44+ T cells may be a subset of memory T cells which retain their capacity of trafficking to inflammatory sites.

Animals↗
PubMed1996

Analysis of anomalous CD44 gene expression in human breast, bladder, and colon cancer and correlation of observed mRNA and protein isoforms.

Many studies have now demonstrated disorganized overexpression of the CD44 gene in various types of human malignant tumors, and this abnormality has emerged as an interesting candidate marker for early cancer diagnosis. The purpose of this work was to analyze and compare the patterns of transcription and translation of this gene in human breast (ZR75-1; MDAMB-435 clone 4A4) and colon (HT29) tumor cell lines and in tumors of the breast, bladder, and colon, with the aim of identifying the most suitable analyte for diagnostic purposes. Transcription was studied by reverse transcription-polymerase chain reaction using CD44-specific primers and probes complementary to exons in the standard (exons 3 to 5 and 16 to 18) and variably expressed regions of this gene (exons 7, 8, 10, 11, and 15). Translation was investigated by Western blot analysis and immunohistochemistry using monoclonal antibodies specific to the standard form of CD44 and to the products of the same variant exons. Southern blot hybridization analysis of the reverse transcription-polymerase chain reaction products showed a large number of CD44 transcripts in tumor cells. Direct comparison of these Southern blots with Western blots on matched tumor-cell-line extracts indicated that most of the diverse mRNA isoforms did not detectably translate into proteins. However, immunohistochemistry of normal and malignant breast (n = 17 and 23, respectively), bladder (n = 5 and 19), and colon (n = 19 and 19) tissue specimens showed increased staining of CD44 standard and CD44 variant proteins in the carcinoma cells. Combination of this information with the data from reverse transcription-polymerase chain reaction and Western blot analysis indicates that the overexpression at the protein level involves only a minority of the aberrant RNA transcripts. We conclude that the development of methods for the accurate quantitation of over-abundant CD44 RNA species in clinical samples offers the most promising approach to improved early diagnosis of malignancy using this new marker.

Antibodies, Monoclonal↗
PubMed1996

Induction of fibroblast apoptosis by anti-CD44 antibody: implications for the treatment of fibroproliferative lung disease.

Fibroblast migration and proliferation within the alveolar wall and airspace after lung injury can lead to the development of fibrosis. Fibroblast cell surface CD44 is an adhesion receptor for provisional matrix proteins and mediates fibroblast invasion into fibrin matrices. Here we show that incubation of cultured fibroblasts with an anti-CD44 monoclonal antibody induces fibroblast detachment from the substratum and morphological changes compatible with apoptosis. In addition, we show that anti-CD44 monoclonal antibody rapidly induces fibroblast apoptosis within fibrin matrices. The effect of anti-CD44 antibody on induction of fibroblast apoptosis occurred within 8 hours and was dose dependent. Anti-CD44 antibody also induced fibroblast apoptosis in suspension. Furthermore, fibroblasts plated on anti-CD44-antibody-coated surfaces initially attached and spread on the antibody; however, after an 8-hour incubation time, many of the cells developed characteristic morphological features of apoptosis. Collectively, these data indicate that apoptosis did not result solely due to detachment from the substratum. Our results identify a new function for fibroblast cell surface CD44 related to the control of cell viability. We suggest this function may be important in fibroblast population control and could potentially be exploited in designing anti-fibrotic therapies.

Antibodies, Monoclonal↗
PubMed1997

CD44-mediated adhesiveness of human hematopoietic progenitors to hyaluronan is modulated by cytokines.

Adhesive interactions between CD34+ hematopoietic progenitor cells (HPC) and bone marrow stroma are crucial for normal hematopoiesis, yet their molecular bases are still poorly elucidated. We have investigated whether cell surface proteoglycan CD44 can mediate adhesion of human CD34+ HPC to immobilized hyaluronan (HA), an abundant glycosaminoglycan of the bone marrow extracellular matrix. Our data show that, although CD34+ cells strongly express CD44, only 13.3% +/- 1.1% spontaneously adheres to HA. Short-term methylcellulose assay showed that HA-adherent CD34+ cells comprised granulo-monocytic and erythroid committed progenitors (19.6% +/- 2.5% and 7.3% +/- 1.0% of the input, respectively). More primitive progenitors, such as pre-colony-forming units, also adhered to HA. Moreover, we found that CD44-mediated adhesion of CD34+ cells to HA could be enhanced by phorbol 12-myristate 13-acetate (PMA), the function-activating anti-CD44 monoclonal antibody H90, and cytokines such as granulocyte-monocyte colony-stimulating factor, interleukin-3 (IL-3), and stem cell factor. Enhancement through PMA required several hours, was protein-synthesis-dependent, and was associated with an increase of CD44 cell surface expression, whereas stimulation of adhesion by H90 monoclonal antibody and cytokines was very rapid and without alteration of CD44 expression. H90-induced activation occurred at 4 degrees C and lasted for at least 2 hours, whereas activation by cytokines required incubation at 37 degrees C and was transient. These data, which show for the first time that CD34+ HPC can directly adhere to HA via CD44, point out that this adhesive interaction to HA is a process that may also be physiologically regulated by cytokines.

ADP-ribosyl Cyclase↗
PubMedDate not supplied

Expression of CD44 in duct cell carcinomas and in intraductal neoplasms of the pancreas.

The expression of alternatively spliced CD44 isoforms, especially so-called variant exons v5 and v6, has been shown to correlate with the progression of a number of human cancers examined the expression of standard CD44 and CD44 variants with exons v5 and v6 in 28 cases of human pancreatic tumors (16 cases of invasive duct cell adenocarcinoma and 12 cases of intraductal neoplasms) by immunohistochemistry using exon specific monoclonal antibodies. The expression of standard CD44 was frequently observed in both invasive duct cell carcinomas and intraductal neoplasms. The expression of CD44 variants (v5 and v6) was also seen in almost all duct cell carcinomas. In contrast, intraductal neoplasms infrequently expressed CD44-v5 and -v6, particularly v6 exon. Expression of CD44-v5 and v6 was a common characteristic of invasive cancer, while it was not so prominent in intraductal neoplasm. These findings may be related to the invasiveness of duct cell carcinoma and/or the benign biological behavior of intraductal neoplasm of the pancreas.

Carcinoma, Ductal, Breast↗
PubMed1997

Expression of CD44 splice variants in colorectal cancer.

BACKGROUND: The CD44 gene codes for a family of heavily glycosylated cell surface proteins that have been linked with tumour metastasis. The aim of the study was to analyse the expression of CD44 messenger RNA in colorectal cancer. METHODS: The expression of CD44 variants 2 and 7 in colorectal tumour samples was compared with that in normal colon and lymphocytes from 59 patients using reverse transcription-polymerase chain reaction followed by blot hybridization with exon-specific probes, and a nested polymerase chain reaction. RESULTS: All samples of tumour and metastatic tissue showed complex overexpression of many alternatively spliced products of the CD44 gene. Normal colon, liver and lymphocytes predominantly expressed the standard form of the CD44 molecule (CD44S) with low levels of two or three variants hybridizing to exons v2 and v7. CONCLUSION: Deranged CD44 gene activity in colorectal cancer cells is confirmed. The analysis of CD44 gene expression may provide a promising marker for the early detection of colonic tumours.

Aged↗
PubMed1997

Changes in CD44 isoform expression during inflammatory skin disease.

The CD44 family of cell surface glycoproteins is widely expressed in epithelial, mesothelial and haemopoietic tissues and is thought to function primarily as adhesion molecules. The molecule has an intracellular, a transmembrane and an extracellular domain. The membrane proximal region of the extracellular domain is of variable structure depending on which of 10 variable exons are involved in coding for this region. Both in vitro stimulated T cells and cytokine stimulated keratinocytes are known to express certain isoforms. In this study we have investigated whether specific isoforms of the CD44 molecule are expressed on epithelial cells and lymphocytes in the course of two inflammatory skin diseases, namely lupus erythematosus and lichen planus. Monoclonal antibodies, specific to the epitopes of the CD44 molecule encoded by v3, v4/5, v6 and v8/9 variable exons and a pan CD44 marker, were used on 10 lupus and 8 lichen planus frozen skin samples and compared with normal skin from 9 different body sites. Results failed to show detectable levels of variant isoforms of CD44 on lymphocytes in either inflammatory skin disease, despite evidence of T cell activation. All CD44 variant isoforms were reduced on the keratinocytes in some sections of lupus and lichen planus. The results are discussed in the context of the current models for the role of CD44 in the immune response.

Humans↗
PubMed1998

CD44 expression in the stromal matrix of colorectal cancer: association with prognosis.

CD44, a cell hyaluronate receptor, is implicated in the metastatic behavior of some cancer cells. This study analyzed CD44 expression in topographic tissue sites of colorectal cancers to determine its association with patient survival and clinicopathological characteristics. Immunohistochemical localization of the core CD44 and the v6 splice variant domains was examined by use of paraffin-fixed sections from 133 stage II or III colorectal cancers that previously had been evaluated for other diagnostic markers. Expression in malignant epithelium, stromal matrix, and stromal cells was compared to patient survival by univariate, multivariate, and bootstrap (reproducibility) analysis. Core CD44 staining was present in the malignant epithelium of 85% of tumors, the stromal matrix of 90%, and the stromal cells of 98%. The v6 splice variant domain was present in the epithelium of 77% of tumors but was less frequent in the stromal matrix (12%; P < 0.001) and stromal cells (17%; P < 0.001). Absence of core CD44 immunoreactivity in the stromal matrix was associated with increased death rate (hazard ratio, 2.4; 95% confidence interval, 1.2-4.8; P = 0.02), making this one of the most significant adverse prognostic variables, along with an age of 60 years or older, poor differentiation of the cancer, extramural venous invasion, chromosome 18q allelic loss, and nonwhite race. This study shows that core CD44 and v6 splice variant antigens are differentially expressed in the epithelium and stroma of colorectal cancers. A model that includes core CD44 immunoreactivity in stromal matrix along with other prognostic factors may improve identification of high-risk and low-risk patients.

Adult↗