Role Of CD44 Expression Research Articles

490P New horizons in metastatic colorectal cancer: Role of CD44 expression

The transmembrane glycoprotein CD44, the major hyaluronan receptor, is considered to be involved in carcinogenesis. Its role as new therapeutic molecular target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival of metastatic colorectal cancer (mCRC) patients (pts).

POS-168 Mosaic Pattern of Progenitor Cell Marker CD133 Expression to Identify Podocyte Proliferation Supports Collapsing Variant of Focal Segmental Glomerulosclerosis (FSGS)

Previous studies using immunofluorescent methods indicate that both the cellular crescents in crescentic glomerulonephritis and the podocyte proliferation in collapsing FSGS may both originate from parietal epithelial cells, which serve as CD133 positive progenitor cells. We have previously confirmed positive CD133 staining in the cellular crescents of crescentic glomerulonephritis. However, the role of CD133 expression in highlighting the proliferative podocytes in collapsing FSGS has not been adapted to the renal pathology practice.

Preclinical evaluation of 89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys

RG7356 is a humanized antibody targeting the constant region of CD44. RG7356 was radiolabeled with 89Zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study of its biodistribution and the role of CD44 expression on RG7356 uptake. Studies with 89Zr-RG7356 were performed in mice bearing tumor xenografts that differ in the level of CD44 expression (CD44+ or CD44-) and RG7356 responsiveness (resp or non-resp): MDA-MB-231 (CD44+, resp), PL45 (CD44+, non-resp) and HepG2 (CD44–, non-resp). Immuno-PET whole body biodistribution studies were performed in normal cynomolgus monkeys to determine normal organ uptake after administration of a single dose. At 1, 2, 3, and 6 days after injection, 89Zr-RG7356 uptake in MDA-MB-231 (CD44+, resp) xenografts was nearly constant and about 9 times higher than in HepG2 (CD44–, non-resp) xenografts (range 27.44 ± 12.93 to 33.13 ± 7.42% ID/g vs. 3.25 ± 0.38 to 3.90 ± 0.58% ID/g). Uptake of 89Zr-RG7356 was similar in MDA-MB-231 (CD44+, resp) and PL45 (CD44+, non-resp) xenografts. Studies in monkeys revealed antibody uptake in spleen, salivary glands and bone marrow, which might be related to the level of CD44 expression. 89Zr-RG7356 uptake in these normal organs decreased with increasing dose levels of unlabeled RG7356.89Zr-RG7356 selectively targets CD44+ responsive and non-responsive tumors in mice and CD44+ tissues in monkeys. These studies indicate the importance of accurate antibody dosing in humans to obtain optimal tumor targeting. Moreover, efficient binding of RG7356 to CD44+ tumors may not be sufficient in itself to drive an anti-tumor response.

The role of CD133 expression in the carcinogenesis and prognosis of patients with lung cancer

Cancer stem cells (CSCs) are a small population of undifferentiated cancer cells within tumors, which contribute to tumorigenicity and relapse. In the current study, CD133 (also termed prominin‑1), a CSC marker, was investigated to determine its involvement in predicting carcinogenesis and prognosis in patients with non‑small cell lung carcinoma (NSCLC). CD133‑positive lung cancer cells were isolated to analyze self‑renewal, differentiation and tumorigenic abilities in vitro and in vivo. Quantitative polymerase chain reaction was used to detect the expression of CD133 and three other CSC‑associated markers, octamer‑binding transcription factor 4 (OCT4A), Nanog homeobox (NANOG) and multidrug resistance protein 1 (MDR1), in primary NSCLC and adjacent non‑cancer tissues. A series of statistical methods were used to analyze the correlation between mRNA expression levels, clinicopathological features and patient survival. The results showed that CD133‑positive NSCLC cells demonstrated clonogenic, tumorigenic and drug‑resistance properties compared with their CD133‑negative counterparts or parental cells. In addition, compared with the adjacent normal lung tissue, the levels of CSC‑associated biomarkers CD133, OCT4A, NANOG and MDR1 were significantly increased in NSCLC tissue. Elevated expression of CD133 was associated with stage, tumor size and differentiation of NSCLC; however, the cox hazard regression analysis showed no significant association between CD133 expression and overall patient survival. The present study supports the hypothesis that the stem cell population can be enriched in cells expressing the CD133 cell surface marker and that highly expressed CD133 is involved in the occurrence of NSCLC. However, CD133 may not be considered as an independent factor in predicting the prognosis of patients with NSCLC. Further studies are required to investigate the association between CD133 expression and overall patient survival.

Abstract 4917: CD44 standard form expression in human ovarian carcinoma is correlated with disease progression but not prognosis.

Abstract Single-chain glycoprotein CD44 is a major cell surface receptor for hyaluronan and mediates epithelial cell adhesion by its involvement in cell-cell and cell-matrix interactions. Recently, CD44 has been identified as a biomarker of cancer stem cells in many malignancies, including ovarian carcinoma. However, its clinical significance in human ovarian carcinoma has been controversial until recently. The aim of our current study was to clarify the clinical role of CD44 expression in ovarian carcinoma. Immunohistochemical staining of 483 human primary ovarian carcinoma, and 27 paired primary and recurrent ovarian carcinoma samples for CD44 standard form (CD44s) was performed using tissue microarray. The associations between CD44s expression and clinical factors (diagnosis, tumor grade, International Federation of Gynecology and Obstetrics stage, and response to chemotherapy) and overall and disease-free survivals were analyzed. We observed CD44s expression in 38.1% of the ovarian carcinoma samples. Results of Fisher's exact test suggested that CD44s expression was associated with high-grade carcinoma (P = 0.013), especially high-grade serous carcinoma (P = 0.037); International Federation of Gynecology and Obstetrics stage (III-IV, P < 0.001); age at diagnosis less than 60 years old (P = 0.011); and transitional cell carcinoma (P = 0.039). However, CD44s expression was not associated with overall survival (P = 0.529) or disease-free survival (P = 0.035) by the log-rank test. Moreover, there was no statistical difference in CD44s expression between the primary and recurrent epithelial ovarian carcinomas. Our results showed that CD44s expression is correlated with tumor progression but not prognosis. Citation Format: Jing Zhang, Bin Chang, Jinsong Liu. CD44 standard form expression in human ovarian carcinoma is correlated with disease progression but not prognosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2013-4917

Abstract A35: A role for drug resistance in hepatocellular carcinoma: Upregulatation of CD133, activation of IGF-1R signaling, and IGF-1R nuclear translocation

Abstract Introduction: Hepatocellular carcinoma (HCC) is an aggressive neoplasm that is resistant to chemotherapy with mechanisms underlying this drug resistance not well understood. CD133 is a known cancer stem cell (CSC) marker whose high expression is associated with aggressive tumor behavior and poor prognosis. The insulin-like growth factor 1 receptor (IGF-1R) signaling pathway has been shown to play a significant role in tumor behavior. To examine possible mechanisms of drug resistance in HCC, we investigated the role of CD133 expression and IGF-1R signaling activation using geftinib. Methods: We evaluated and separated five different human HCC cell lines (Mahlavu, Huh7, HepG2, Hep3B, PLC/PRF/5) using based on CD133 expression. We subjected these cells to geftinib at different doses, and determined IGF-1R signaling pathway activation using immunoblotting against relevant proteins in the pathway. CD133 mRNA level was examined using quantitative real-time PCR and its expression level was detected using immunofluorescence imaging and flow cytometry after drug treatment. Cell viability and sensitivity to drug treatment were measured using the MTT assay. Results: HCC cell lines showed variable percentages of total cell populations expressing CD133: Mahlavu 0.12 %, HepG2 46 %, Huh7 80.2 %, Hep3B 98.2 %, and PLC/PRF/5 83.5 %. Mahlavu and PLC/PRF/5 were found to be the most resistant cell lines even at higher doses (17.5 uM). Since Mahlavu cells displayed reduced CD133 expression, experiments were focused on this cell line to evaluate the CD133 expression changes after geftinib treatment. After three rounds (9 days) of high dose geftinib treatment, CD133 expression was increased in a dose dependent manner; the percentages of total cell populations expressing CD133 increased to 43.9 % at 10 uM concentration and 52.9 % at 15 uM concentration as compared to 0.12 % in untreated cells. In addition, we found a significant increase in IGF-1R and AKT phosphorylation as well as IGFBP3 expression in those geftinib treated cells. Furthermore, after cell sorting of Huh7 cells by CD133 expression using flow cytometry, we observed that CD133 positive cells showed more resistant to geftinib treatment. Immunofluorescence imaging analysis demonstrated that increased IGF-1R protein translocated to nuclei after geftinib treatment. Conclusion: Geftinib treatment enhanced CD133 expression level and activated IGF-1R signaling in HCC Mahlavu cells, one of the possible mechanism could be the nuclear translocation of IGF-1R. Our findings underscore the importance of a combined therapeutic approach with geftinib and IGF-1R blockage in the treatment of human HCC. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A35.

CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression.

To clarify the possible role of CD44 expression in ovarian tumour development and progression, an immunohistochemical investigation was undertaken of a series of 115 carcinomas, 32 tumours with low malignant potential (LMP), and 53 cystadenomas. A combination of the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) assays was also performed for 17 malignant, four LMP, six cystadenoma, and seven normal ovarian samples. Immunoreactivity scores for CD44s, CD44v3, and CD44v6 were significantly higher in LMP and malignant tumours than in the benign or normal cases, in line with the results of gross mRNA-based assays. Exon-specific RT-PCR/SBH assays revealed that the expression of large CD44 transcripts containing v6 to v8 exons and small isoforms containing v2 and v3 was common among normal and neoplastic tissues, while a simultaneous increase of large isoforms containing v2 to v5 was also revealed in LMP and malignant tumours. In ovarian carcinomas, the scores for CD44s, CD44v3, and CD44v6 were inversely related to the FIGO stage, but there was no association with lymph node status or expression of hormone receptors. Multivariate analysis revealed loss of CD44v3 expression to be an independent factor for poor survival. The findings indicate that CD44 is up-regulated during the development of ovarian carcinomas but is subsequently down-regulated during their progression, resulting in aggressive behaviour and an unfavourable prognosis.

CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression

To clarify the possible role of CD44 expression in ovarian tumour development and progression, an immunohistochemical investigation was undertaken of a series of 115 carcinomas, 32 tumours with low malignant potential (LMP), and 53 cystadenomas. A combination of the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) assays was also performed for 17 malignant, four LMP, six cystadenoma, and seven normal ovarian samples. Immunoreactivity scores for CD44s, CD44v3, and CD44v6 were significantly higher in LMP and malignant tumours than in the benign or normal cases, in line with the results of gross mRNA-based assays. Exon-specific RT-PCR/SBH assays revealed that the expression of large CD44 transcripts containing v6 to v8 exons and small isoforms containing v2 and v3 was common among normal and neoplastic tissues, while a simultaneous increase of large isoforms containing v2 to v5 was also revealed in LMP and malignant tumours. In ovarian carcinomas, the scores for CD44s, CD44v3, and CD44v6 were inversely related to the FIGO stage, but there was no association with lymph node status or expression of hormone receptors. Multivariate analysis revealed loss of CD44v3 expression to be an independent factor for poor survival. The findings indicate that CD44 is up-regulated during the development of ovarian carcinomas but is subsequently down-regulated during their progression, resulting in aggressive behaviour and an unfavourable prognosis. Copyright © 1999 John Wiley & Sons, Ltd.