Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The designation CD44 describes a group of type I transmembrane proteins which share N-terminal and C-terminal sequences. These molecules differ in the central extracellular domain by the use of sequences encoded by ten variant exons which may be completely absent or included in various combinations and by cell type specific addition of glycosaminoglycan and carbohydrate moieties. Expression of variant proteins is observed in normal tissues such as on keratinocytes, dendritic cells and activated lymphocytes in the adult organism and on morphogenetically active epithelium such as the apical ectodermal ridge (AER) in the embryo. Certain CD44 proteins expressed on the AER can act as low affinity fibroblast growth factor receptors and are vital for epithelial-mesenchymal cell communication. CD44 variant proteins have also been implicated in tumour growth and metastasis and we speculate that CD44 mediated growth factor presentation may also be decisive in metastasis formation. Molecular strategies designed to block growth factor presentation by CD44 may aid in the therapy of metastatic cancer.
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PMID:The CD44 protein family. 961 72

Lymph node metastasis is a critical prognostic factor for gastric cancer. In the present investigation we examined clinicopathologic factors influencing the metastatic processes to the lymph mode and their prognostic importance. A randomly selected group of 98 patients with adenocarcinomas of the stomach who underwent gastrectomy plus systematic lymph node dissection at Osaka Police Hospital from 1991 to 1996 were analyzed. Altogether 37 (38%) cancers were positive for CD44 variant 6 (v6) staining, 31 (32%) were intermediately stained, and 30 (30%) were negative. CD44-v6 expression correlated well with lymph node metastasis. Expression of CD44-v6 and lymphatic invasion were independent risk factors for metastatic lymph nodes. Among the patients with CD44-v6-positive and lymphatic invasion-positive cancers, 88% had lymph node metastasis, whereas only 13% of patients negative for both factors had lymph node metastasis. Although CD44-v6 expression and lymphatic invasion have been reported to be risk factors for recurrence and a poor prognosis, in this investigation these factors were found not to be significant for hematogenous and lymphatic recurrences or overall survival rates. Thus expression of CD44-v6 and lymphatic invasion may regulate lymph node metastases from gastric cancer.
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PMID:Expression of CD44 variant 6 and lymphatic invasion: importance to lymph node metastasis in gastric cancer. 967 58

Expression of CD44 isoforms has been reported to be involved in tumor invasion and metastasis in both rodents and man. We earlier documented establishment of rat transplantable thyroid carcinoma lines in vivo from primary lesions induced by a chemical carcinogen. Recently, two lines (L1a-M4 and L2a-M6) were found to spontaneously metastasize to the lung after subcutaneous transplantation. To determine whether CD44 splice variants contribute to their metastatic spread, carcinoma lines with and without lung metastasis were evaluated quantitatively and qualitatively using RT-PCR followed by hybridization and immunohistochemical analyses. The L1a-M4 and L2a-M6 metastatic lines showed significant overexpression of CD44 variant transcripts containing variant exons v4-v6 or v9-v10/v8-v10, respectively, with concomitant reduced levels of standard transcripts. Investigation of the precise composition of alternatively spliced mRNA in normal tissues and carcinoma lines using an exon-specific RT-PCR method, revealed major chain variant transcripts containing v2/v3, v4-v6, v7-v10 and v8-v10 in all specimens. Applying the same RT-PCR analysis to mRNAs derived from cultured cell lines, demonstrated essentially the same pattern. The results suggest that quantitative increase rather than qualitative change in CD44 variant isoforms is associated with the pathogenesis of lung metastasis of rat thyroid carcinomas.
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PMID:Overexpression of CD44 variant transcripts in rat transplantable thyroid carcinoma lines demonstrating lung metastasis. 968 85

Up-regulation of CD44 variant isoforms has been linked to the progression of epithelial tumors and the metastatic phenotype. Here we report a functional role for CD44 variant isoforms in colorectal cancer metastasis. An antisense mRNA approach was used to down-regulate CD44 variant isoforms containing CD44 variant 6 (v6) in the metastatic colorectal tumor cell line HT29. Cell lines stably expressing antisense CD44 exon 10 (v6) showed reduced expression of alternatively spliced CD44 variant isoforms but no significant change in expression of CD44 core protein, as judged by immunohistochemical analysis using CD44 domain-specific monoclonal antibodies. Expression of antisense exon 10 (v6) had no effect on HT29 tumor cell proliferation in vitro or the ability of the cells to bind immobilized hyaluronan, but it resulted in a reduced capacity to form liver metastases in nude mice following intrasplenic injection. Metastases were not detected in nude mice inoculated with antisense CD44 exon 10 (v6)-expressing cell lines after 4 months, against a background of a 30% metastasis rate in the control HT29 parental and vector alone transfected lines. Furthermore, whereas 82% of mice intrasplenically injected with control HT29 parental and vector alone cell lines developed tumors in incisional wound sites, none of the mice injected with antisense exon 10 expressing HT29 cells developed similar tumors. This is the first demonstration that antisense RNA can be used to selectively inhibit expression of specific domains of a molecule generated through alternative mRNA splicing while allowing expression of core domains to remain unaffected. Furthermore, these results provide direct evidence for a functional role of CD44 variant isoforms in the metastasis of human colorectal tumor cells and may suggest a critical role for CD44 variants in promoting cell growth specifically in the cytokine/growth factor-enriched environment of a wound site.
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PMID:Expression of antisense CD44 variant 6 inhibits colorectal tumor metastasis and tumor growth in a wound environment. 972 84

The aim of this study is to investigate the predictive value of proliferative activity assessment and E-cadherin expression by means of immunohistochemistry in identifying patients with laryngeal squamous cell carcinoma at a high risk for occult node metastasis. Thirty consecutive patients treated for laryngeal carcinoma with false clinically negative nodes (occult metastases, pN+) between the years 1980 and 1990 were selected for this study. A group of 30 cases with negative cervical lymph nodes (pN-) having a similar anatomic site and tumor size distribution was used as control. In each case, several histological parameters, including grade, pattern of invasion, number of mitosis (x10 high-power field), tumor inflammatory infiltrate, and tumor sclerosis, were assessed. Proliferative activity was determined using immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and MIB-1. Other putative prognostic factors investigated at the immunohistochemical level were the cell adhesion molecule E-cadherin and two oncoproteins, p53 and c-erbB-2. In pN+ cases, the expression of PCNA and MIB-1 was significantly higher than in the pN- group. Moreover, a significant loss of E-cadherin expression was observed in carcinomas with occult metastases. No differences in p53 and c-erbB-2 oncoproteins were found between pN+ and pN- cases. Among the other pathological parameters examined, only histological grade was significantly associated with the presence of occult metastases, but on multivariate analysis, this relationship was lost. We conclude that PCNA, MIB-1, and E-cadherin are independent predictors of occult nodal disease in laryngeal squamous cell carcinoma, and their immunohistochemical determination could be useful in identifying patients with clinically negative lymph nodes who are at considerable risk for occult metastases and who may benefit from elective neck dissection.
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PMID:Prediction of occult neck metastases in laryngeal carcinoma: role of proliferating cell nuclear antigen, MIB-1, and E-cadherin immunohistochemical determination. 981 33

In a variety of human tumors, expression of splice variants of the adhesion molecule CD44 (CD44v) has been described as correlating with tumor progression. Here, we report on the expression of CD44v in melanocytes, nevi, primary melanomas, and cutaneous and lymph node metastases. Thirteen nevi, 65 primary melanomas of varying thickness, 39 cutaneous and 15 lymph node metastases, and melanocytes and a panel of melanoma lines were tested for surface expression of the standard form of CD44 and the variant exons v5, v6, v7, v7-v8, and v10 by immunohistology or fluorescence-activated cell sorting. Melanocytes did not express any variant isoform of CD44. However, nevi, as well as primary melanoma and melanoma metastases, stained to a varying degree with anti-CD44v5, anti-CD44v7-v8, and anti-CD44v10. Exons v6 and v7 were not detected on any of these tissue specimens. Compared with nevi, expression of exon v10 was up-regulated in thick primary tumors and skin metastases. Lymph node metastases displayed elevated levels of exon v5. Expression of CD44v in melanoma lines (n = 20) differed, inasmuch as many lines did not express variant isoforms; in particular, exon v10. Interestingly, however, the few CD44v5-positive melanoma lines metastasized in the nu/nu mouse. Because benign as well as malignant growth of melanocytes was accompanied by expression of CD44 variant isoforms, a linkage between expression of CD44 variant isoforms and malignant transformation or tumor progression was excluded. Considering the function of distinct isoforms, one might speculate that expression of exon CD44v5, which was up-regulated in lymph node metastases compared with nevi and primary melanoma, provided a growth stimulus. Exon v10 is present at high density in epidermal cells. The de novo expression of this exon in nevi and the increased expression in thick melanoma and skin metastases would be in line with the assumption of an anchoring advantage in the surrounding epidermal tissue.
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PMID:Expression of CD44 variant isoforms in malignant melanoma. 981 90

The prognosis for pancreatic cancer is extremely poor, because there are usually invasion of surrounding tissues and metastases to lymph nodes, liver or peritoneum at the time of diagnosis. Many studies from the molecular-biological stand point have demonstrated this poor prognosis. However, the mechanisms underlying these invasive and metastatic capabilities have not yet been clarified. We reviewed several reports for prognostic factors of pancreatic cancer in molecular-biological examinations, and introduced our recent study on the adhesion molecule CD44. 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 v6 and v2 was observed only in tumor cells, if at all. The expression of CD44 v6 and v2 was correlated with decreased overall survival. A significant correlation was obtained between CD44 v2 and vessel invasion. These results suggest that CD44 v2 and CD44 v6 may be useful markers of a poor prognosis.
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PMID:[The prognostic factors of pancreatic cancer--adhesion molecule CD44]. 983 4

E-cadherin is a cell-cell adhesion molecule involved in tumour invasion and metastasis. We evaluated E-cadherin expression immunohistochemically in 43 formalin-fixed, paraffin-embedded specimens of pancreatic cancer and investigated its relationship to histopathological features. In non-cancerous pancreatic cells E-cadherin immunoreactivity was localized at the cell membrane, particularly at the intercellular junctions. Abnormal E-cadherin expression was found in 18 (42%) cases. A significantly higher proportion of poorly-differentiated tumours (71%) showed abnormal E-cadherin expression compared with moderately (50%) and well (19%) differentiated tumours (P = 0.037). There was a significant correlation between abnormal E-cadherin expression and lymph node involvement (P = 0.013), the presence of distant metastases (P = 0.034) and advanced tumour stage (P = 0.025). These findings suggest that loss of normal E-cadherin expression is involved in the progression of pancreatic cancer.
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PMID:Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. 989 64

CD44v6 expression appears to be associated with adverse prognosis and propensity for metastasis in patients with colorectal cancer. However, expression of CD44 variants in different tumour stages has been poorly characterised. CD44 variant expression was investigated in normal colonic mucosa (n = 36), colorectal adenomas (n = 15), carcinomas (n = 62) and metastases (n = 6) by reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting with exon-specific probes. High frequencies of CD44 standard (CD44s) and CD44 epithelial (CD44e) were observed in normal and neoplastic tissue. CD44v2 was seen predominantly in adenomas (27%) and UICCI carcinomas (29%). CD44v5 expression was low in normal mucosa (3%), higher in adenomas and carcinomas (29-33%), independent of tumour stage. CD44v6 expression was low in normal mucosa (6%) and higher in adenomas (47%) and carcinomas (42%). Surprisingly, a significant decrease of CD44v6 was observed in metastatic primary tumours (8%) and metastases (17%) (UICCIV) (P < or = 0.05). Therefore, the concept of CD44v6 conferring metastatic potential to malignant cells cannot be supported by our data.
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PMID:Decreased expression of CD44 splicing variants in advanced colorectal carcinomas. 989 37

The purpose of this prospective study was to evaluate the expression of CD44 splice variant epitopes in human breast cancer and their potential as prognostic indicators. Invasive breast cancer tissues obtained from 91 patients were examined for expression of the standard CD44 antigen and variant CD44 antigens (v5, v6, v7, v7-v8, and v8-v10) by immunohistochemical staining to investigate the relations of these antigens to clinicopathological factors and prognosis. The expression of standard CD44 antigen was detected in 54.9% of 91 patients with primary human breast cancer. The variant epitopes of CD44 examined, i.e., v5, v6, v7, v7-v8, and v8-v10, were expressed in 54.9%, 54.9%, 0%, 34.1%, and 0%, respectively. There was a significant difference in tumor size, lymph nodal status, and degree of lymphatic permeation between patients who were positive for exon v7-v8 and those negative for this variant (p < 0.01). Prognosis was also significantly worse in patients positive for CD44 v7-v8 than in those negative for this variant. However, multivariate analysis with the three prognostic indicators tumor size, lymph nodal status, and the degree of lymphatic invasion, has shown that the expression of CD44 v7-v8 antigen in breast carcinoma was not a significant independent prognostic factor and was closely dependent on lymphatic invasion and nodal status. Fourteen of 31 patients who were positive for CD44 v7-v8 experienced recurrences. The mode of recurrence was lymphatic metastasis in 10 out of these 14 patients. Breast cancer cells expressing v7-v8 CD44 antigen have an extremely high affinity for lymph nodes and lymphatic vessels, and are likely to metastasize to distant lymph nodes even at a very early stage in the progression of this disease. This suggests that not only the anatomical factors but also organ affinity plays an important role in the establishment of lymph nodal metastasis of breast cancer.
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PMID:The expression of variant exon v7-v8 CD44 antigen in relation to lymphatic metastasis of human breast cancer. 1032 95


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