Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group‐related antigens

Zhang, Shengle; Zhang, Helen S.; Cordon‐Cardo, Carlos; Reuter, Victor E.; Singhal, Anil; Lloyd, Kenneth O.; Livingston, Philip O.

doi:10.1002/(sici)1097-0215(19970926)73:1<50::aid-ijc9>3.3.co;2-o

Cited by 96 publications

(134 citation statements)

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“…Most likely, this is due to the high prevalence of high EpCAM expression in the gastric adenocarcinomas. The differential expression of EpCAM in normal versus neoplastic gastric and esophageal tissue observed in this study is in accordance with other studies, 11,16,27 except for one study reporting strongly positive stained normal gastric epithelium. 15 Because various immunohistochemical studies are difficult to compare due to, e.g., different antibodies used, additional RT-PCR was performed here.…”

Section: Discussionsupporting

confidence: 93%

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

et al. 2001

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Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie / adenovirus receptor ( CAR ), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor -specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule ( EpCAM ) between normal and ( pre )malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber -knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM -targeted vectors. This study thus indicates that EpCAM -targeted adenoviral vectors may be useful for gastric and esophageal cancer ± specific gene therapy in patients. Cancer Gene Therapy ( 2001 ) 8, 342 ± 351

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Section: Discussionsupporting

confidence: 93%

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

et al. 2001

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“…19,20,40 Various immunohistochemical studies have reported MUC2 positivity in colorectal cancers ranging from 21 to 63%. 19,39,[41][42][43] MUC5AC expression has been reported in 13-64% carcinomas, 16,42,44,45 with highest levels of expression in microsatellite-unstable/mismatch repair-deficient tumors 18,19,46 and those showing characteristic mucinous phenotype. 19,47 MUC5B and MUC6 expression in the lower gastrointestinal tract has remained relatively unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…MUC5B has been detected in normal colon where expression appears to be restricted to goblet cells, 15,48 and in the only study to date, MUC5B expression in 3/8 colorectal cancers was diffusely and strongly positive. 44 Similarly, MUC6 expression in colorectal tumors has been restricted largely to adenomas and serrated polyps, the latter have been found to express MUC6 commonly, 30,49 whereas several groups have reported MUC6 expression in cancers as rare or absent, 16,50,51 even in mucinous carcinomas. 52 In 1999, Toyota et al 53 described the existence of the CIMP in colorectal carcinoma, in which hypermethylation is induced in a wide variety of genes.…”

Section: Discussionmentioning

confidence: 99%

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

et al. 2013

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Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (425% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all Po0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.

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“…EpCAM (CD326) is expressed at high level and with high frequency on differentiated cancer cells of most human adenocarcinoma and certain squamous cell carcinoma (13,14,(27)(28)(29). A number of studies have recently used anti-EpCAM antibodies for isolation of so-called cancer stem cells from human breast, colon, pancreas, and prostate tumor tissues (16)(17)(18)30), indicating that EpCAM is also expressed on cancer stem cells.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Amann¹,

Brischwein²,

Lutterbuese³

et al. 2008

Cancer Research

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EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibodybased immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 Mg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 Mg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development. [Cancer Res 2008;68(1):143-51]

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Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group‐related antigens

Cited by 96 publications

References 0 publications

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

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