New Markers of Pancreatic Cancer Identified Through Differential Gene Expression Analyses: Claudin 18 and Annexin A8

Karanjawala, Zarir E.; Illei, Peter B.; Ashfaq, Raheela; Infante, Jeffrey R.; Murphy, Kathleen M.; Pandey, Akhilesh; Schulick, Richard; Winter, Jordan; Sharma, Rajni; Maitra, Anirban; Goggins, Michael; Hruban, Ralph H.

doi:10.1097/pas.0b013e31815701f3

Cited by 120 publications

(108 citation statements)

References 48 publications

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“…This was already implied by previous data (23), showing significant levels of antibody labeling in 50% of pancreatic cancer specimens, including early lesions, such as pancreatic intraepithelial neoplasia. We showed for the first time that CLDN18.2 is a pan-cancer target and is aberrantly activated in neoplasias of the lung, ovary, and esophagus.…”

Section: Discussionsupporting

confidence: 74%

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

Şahin

Koslowski²,

Dhaene³

et al. 2008

Clinical Cancer Research

269

285

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Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. Experimental Design:We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage^specific cell surface molecules and to validate them as therapeutic antibody targets. Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP^responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.Gastroesophageal and pancreatic cancers are among the malignancies with the highest unmet medical needs (1). Gastric cancer is the second leading cause of cancer death worldwide. In 2002, f1.4 million people worldwide developed gastroesophageal cancers and 1.1 million died (2). Esophageal cancer incidence has increased in recent decades, coinciding with a shift in histologic type and primary tumor location. Adenocarcinoma of the esophagus is now more prevalent than squamous cell carcinoma in the United States and Western Europe, with most tumors located in the distal esophagus (3).The overall 5-year survival rates for gastroesophageal cancers are 20% to 25% despite the aggressiveness of established standard treatments associated with substantial side effects (4, 5). For pancreatic cancer, there is an even greater medical need. Due to the advanced state of the disease at the time of diagnosis, the prognosis is extremely poor, with median survival times of less than 6 months and a 5-year survival rate of <5.5%. The lack of a major benefit from the various newergeneration combination chemotherapy regimens for these cancers has stimulated research into the use of targeted agents, such as small molecule -based kinase inhibitors and monoclonal antibodies (mAb; ref. 6). However, mAbs, such as bevacizumab, cetuximab, and trastuzumab...

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Section: Discussionsupporting

confidence: 74%

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

Şahin

Koslowski²,

Dhaene³

et al. 2008

Clinical Cancer Research

269

285

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“…Nonetheless, because of the high specificity of claudin expression patterns that has been demonstrated in cancer tissue so far, it was proposed that claudins might represent useful diagnostic and prognostic markers for various cancers. [11][12][13][14][15][16] Namely, claudins have been identified not only as a useful immunohistochemical markers in distinguishing different variants of neoplasms, [11][12][13] but their expression was also found to correlate with prognosis in several cancers. [14][15][16] However, at present only a subset of claudin isoforms have been investigated in a relatively limited number of human cancers.…”

mentioning

confidence: 99%

The diagnostic and prognostic utility of claudin expression in renal cell neoplasms

et al. 2008

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This study evaluated the expression patterns of claudins 1, 3, 4, 7, and 8 in human renal cell carcinomas and oncocytomas and correlated expression with patient prognosis. Tissue microarrays were created from paraffinembedded tissue samples from 141 patients with renal cell carcinomas or oncocytoma (90 clear cell, 22 papillary, 17 chromophobe renal cell carcinomas, and 12 oncocytomas). The staining pattern for claudins 3, 4, 7, and 8 was membranous and/or cytoplasmic, whereas claudin 1 was predominantly membranous in both nonneoplastic renal tissue and tumors. Negative to weak claudin 3 staining was predominantly detected in Fuhrman's grade 1 and 2 clear cell renal cell carcinomas (78%; P ¼ 0.016), suggesting that upregulation of claudin 3 potentially occurs concomitantly with increasing grade of clear cell renal cell carcinomas. In addition, Kaplan-Meier univariate analysis showed a significant inverse correlation between moderate to strong claudin 3 and 4 expression with overall survival in clear cell renal cell carcinomas (P ¼ 0.038 and P ¼ 0.031). Moderate to strong claudin 7 expression was significantly more common in chromophobe renal cell carcinomas (94%) than in oncocytomas (55%; P ¼ 0.041). Claudin 8 staining was moderate to strong in 92% of oncocytomas, which differentiated them from papillary and clear cell renal cell carcinomas (14 and 12%; both Po0.0001). Only negative to weak claudin 8 staining was detected in all chromophobe renal cell carcinomas, whereas there were no claudin 8 negative oncocytomas and 8% exhibited a weak staining pattern (Po0.0001). Due to their distinctive expression patterns, claudins 7 and 8 can be used as useful immunohistochemical markers for the separation of chromophobe renal cell carcinomas from oncocytomas, whereas claudins 3 and 4 may serve as indicators of prognosis in clear cell renal cell carcinomas.

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“…The epithelial cells showed intracellular mucin accumulation ( Figure 1H and Supplemental Figure 2D) and strong positive staining of membrane claudin-18, a marker that specifically differentiates PanIN and PDA from reactive ducts in human and mouse (Supplemental Figure 2E and refs. 21,22); thus, we identify them as PanINs and refer to them as such herein. Our classification of these morphologic lesions as PanINs is consistent with previous publications using the cerulein model (19,20) and activation of oncogenic Kras* in adult animals (23).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Collins

Bednar²,

Zhang³

et al. 2012

J. Clin. Invest.

655

633

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Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRAS G12D , that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible Kras G12D , which allows for inducible, pancreas-specific, and reversible expression of the oncogenic Kras G12D , with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic Kras G12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of Kras G12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that Kras G12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, Kras G12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial Kras G12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting Kras G12D , or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.

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New Markers of Pancreatic Cancer Identified Through Differential Gene Expression Analyses: Claudin 18 and Annexin A8

Abstract: Background-New markers to distinguish benign reactive glands from infiltrating ductal adenocarcinoma of the pancreas are needed.

Cited by 120 publications

References 48 publications

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

The diagnostic and prognostic utility of claudin expression in renal cell neoplasms

Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

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