Expression of CD44 Variants and Its Association with Survival in Pancreatic Cancer

Abstract

Since the CD44 variant 6(v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors, we examined whether or not v6 is a useful marker for evaluating the prognosis of pancreatic cancer patients. In addition, we attempted to assess the clinicopathological implications for pancreatic cancer of the variant 2 (v2) isoform using a recently developed monoclonal antibody against a v2 epitope. The expression of CD44 variants was evaluated immunohistochemically in paraffin-embedded pancreatic cancer tissues from 42 patients who were confirmed surgically and histologically to have received curative resection. An indirect immunoperoxidase method was used with monoclonal antibodies against epitopes of the standard (CD44s) Key words: CD44 variants -Pancreatic cancer -Metastasis -Prognosis -Immunohistochemistry CD44 is a heavily glycosylated cell surface molecule which is involved in cell-cell and cell-matrix interactions 1, 2) and mediates several functions, such as extracellular matrix cell adhesion, 3, 4) lymphocyte homing, 5,6) T cell activation 7) and tumor metastasis. 7,8) The CD44 family of polymorphic transmembrane glycoproteins is encoded by a complex gene 7,[9][10][11][12] that occupies a stretch of 60-80 kD assigned to the human chromosomal locus 11p13. Its human form is composed of at least 21 exons, 10 of which are constitutively expressed on almost all cell types to produce a heavily glycosylated 85-90 kD isoform known as standard form CD44s (Fig. 1). The remaining exons can be alternatively spliced in various combinations, and their products are incorporated into the polypeptide backbone encoded by the standard form exons. This results in a large array of protein isoforms (CD44v) which are differentially expressed in various tissues and at various stages in development. 13)Recently, it was demonstrated that the expression of one variant isoform of CD44 distinguished metastatic from non-metastatic pancreatic carcinoma cell lines in the rat.8) Evidence that CD44v itself has a role in metastasis came from the demonstration that transfection with cDNA encoding this isoform converted non-metastatic carcinoma rat cells into metastatic cells. 8) Although the functions of CD44v isoforms in humans remain unclear, it is thought that CD44v isoforms play an important role in the growth and metastasis of several kinds of tumors. [14][15][16][17][18] It has been demonstrated that the disturbed activity of the CD44 gene in malignant tumors results in the accumulation of immature mRNA transcripts containing introns 10,19) from the CD44 gene. Moreover, in a recent study, 20) direct comparison of Southern blots with western blots from matched tumor cell line extracts indicated that most of the diverse mRNA isoforms are not detectably translated into proteins. These findings, together with data from reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, show that the overexpression at the protein level involves only a minority of aberrant RNA transcripts.Recent clinic...

CD44 Attenuates Metastatic Invasion during Breast Cancer Progression

“…Several studies have associated CD44 expression with tumor progression and metastasis, whereas others maintain that CD44-positive cells exhibit a favorable prognosis. Studies have found increased levels of CD44 variant isoform expression correlating with poor prognosis in diseases, such as thyroid cancer, prostate cancer, renal cell carcinoma, and breast cancer; whereas others have shown decreased levels of CD44 correlating with good prognosis in head and neck carcinomas, prostate, colon cancer, breast cancer, and neuroblastoma (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). In vitro data showing that the effects of CD44 engagement with hyaluronan during cancer progression and metastatic spread seem cell type specific and dependent upon CD44 isoform expression.…”

Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist

“…The cell adhesion molecule CD44 is a transmembrane glycoprotein overexpressed and linked to bad prognosis in a number of tumor entities such as breast (1)(2)(3) and pancreatic cancer (4,5), hepatocellular carcinoma (6) and hematologic malignancies (7). CD44 receptor varies in size and function owing to N-and O-glycosylation and alternative splicing, which affects predominantly the extracellular domain of the protein.…”

Clinicopathological Significance of Expression of CD44 Variants in Head and Neck Squamous Cell Carcinoma

“…Additionally, using a recently developed monoclonal antibody against a CD44v2 epitope, we have demonstrated that CD44v2 expression was correlated significantly with poorer prognosis in breast cancer 15) and in pancreatic cancer. 16) Other reports show that the expression of CD44st is associated with longer survival in neuroblastoma 17) and that down-regulation of CD44v6 is associated with shorter survival in laryngeal squamous cell carcinoma. 18) We have proved that down-regulation of CD44v2 was correlated significantly with poorer prognosis in esophageal squamous cell carcinoma.…”