Molecular Characterization of a Tissue‐Polypeptide‐Specific‐Antigen Epitope and its Relationship to Human Cytokeratin 18

Rydlander, L.; Ziegler, E; Bergman, Tomas; Schöberl, Eva; Steiner, Georg; Bergman, Anders; Zetterberg, Anders; Marberger, Michael; Björklund, Peter; Skern, Tim; Einarsson, R.; Jörnvall, Hans

doi:10.1111/j.1432-1033.1996.00309.x

Cited by 84 publications

(52 citation statements)

References 21 publications

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“…3A, bottom). A 13-kDa CK18 form (CK18 residues 284-396) has been described in culture medium from apoptotic cells (22), consistent with the present findings. Injection of a recombinant 13 kDa fragment i.v.…”

Section: Methodssupporting

confidence: 82%

Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy

Olofsson

Ueno

Pan

et al. 2007

Clinical Cancer Research

134

123

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Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer. Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/ epirubicin/5-fluorouracil (CEF) therapy. Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P < 0.0001).Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracyclinebased therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.

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Section: Methodssupporting

confidence: 82%

Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy

Olofsson

Ueno

Pan

et al. 2007

Clinical Cancer Research

134

123

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“…Increased levels of intact and fragmented K8/K18, initially identified as tissue-polypeptide antigen, have been reported in sera of cancer patients, and several clinical studies have found increased levels of tissue-polypeptide antigen in various cancers, including colon, breast, and prostate (45)(46)(47). Furthermore, a kit (CYFRA 21-1, Roche Diagnostics) is currently being marketed in some parts of Europe for specific detection of a lung cancer-associated K19 fragment (48,49).…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated Cleavage of Cytokeratin 8/18 Heterotypic Complexes Exposes a Neoepitope in Human Adenocarcinomas

Ditzel¹,

Strik²,

Kobæk-Larsen³

et al. 2002

Journal of Biological Chemistry

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The intermediate filament network in simple glandular epithelial cells predominantly consists of heterotypic complexes of cytokeratin 8 (K8) and cytokeratin 18 (K18). In contrast to other cytokeratins, K8 and K18 are persistently expressed during malignant transformation, but changes in cell morphology are accompanied by alterations in the intermediate filament network. To study molecular changes, K8 and K18 were purified from surgically removed colon cancer and normal epithelia tissues. Western blotting and amino acid sequencing revealed the presence of abundant K8 and K18 fragments, truncated at the N terminus, from cancerous, but not normal, epithelial cells. The fragmentation pattern indicates proteolysis mediated by several enzymes, including trypsin-like enzymes. The cancer-associated forms of K8 and K18 are specifically recognized by the human antibody, COU-1, cloned from the B cells of a cancer patient. We demonstrate that COU-1 recognizes a unique conformational epitope presented only by a complex between K8 and K18. The epitope is revealed after proteolytic removal of the head domain of either K8 or K18. A large panel of recombinant K8 and K18 fragments, deleted N-or C-terminally, allowed for the localization of the COU-1 epitope to the N-terminal part of the rod domains. Using surface plasmon resonance, the affinity of COU-1 for this epitope was determined to be 10 9 M ؊1 , i.e. more than 2 orders of magnitude higher than for intact heterotypic K8/K18 complexes. The cellular distribution of truncated K8/K18 heterotypic complexes in viable adenocarcinomas cells was probed using COU-1 showing small fibrillar structures distinct from those of intact K8/K18 complexes. Previously we demonstrated the binding and subsequent internalization of recombinant Fab COU-1 to live cancer cells. We have thus characterized a cancer neoepitope recognized by the humoral immune system. The results have biological as well as clinical implications.The 10 nm intermediate filaments (IF) 1 provide resilience in response to mechanical stress by forming a stable network attached to specific desmosome cell-cell contacts (1). IF can be classified into groups expressed in higher eukaryotes in a tissue-specific and cell type-restricted pattern (2, 3). In epithelial cells, IFs consist of stoichiometrically equal amounts of type I (smaller and acidic) and type II (larger, neutral, or basic) cytokeratin polypeptides, which form strongly interacting heterodimers (4 -6). Cytokeratin 8 (K8) and cytokeratin 18 (K18), type I and II, respectively, are the major components of IFs of simple or single layer epithelia, such as those of the intestine, the liver, and the breast ducts, although cytokeratin 19 (K19) is also present and forms heterodimers with K8 (2, 5). The assembly of IF involves several association steps where the ␣-helical rod domain of the cytokeratin molecules plays the central role (7-9). The head and the tail domains are not thought to be part of the filamentous backbone but to protrude laterally and contribute to profilame...

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“…Moreover, cytokeratin is an acid type intermediate filament protein detected in various types of human cancer. Tissue polypeptide specific antigens (TPS), which measures M 3 antigenic determinant associated with human cytokeratin 18, is a marker of tumor cell activity in contrast to markers related to tumor burden (Rydlander et al, 1996). In breast cancer management, there is an improved effectiveness can be seen when TPS is used in combination with CA15-3 (Hwa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Correlation of Preoperative Serum Tumor Markers with Clinicopathological Features and Prognosis in Breast Cancer

Zheng¹,

Chen²,

Hu³

et al. 2012

CCO

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Background: Serologic tumor markers such as CA15-3, CEA and TPS have been used for decades to manage patients with breast cancer. Despite the frequent use of these markers, the prognostic significance of these markers remains indeterminate. Patients and methods: We retrospectively analyzed and followed up a set of 361 patients with Stages I~III breast cancer, from January 2001 to February 2011. Serumal CA15-3 and CEA levels were measured by electrochemistry (ELC), and serumal TPS was analyzed by enzyme-linked immunosorbent assays (ELISA). We explored the relationship between preoperative serologic tumor markers and clinicopathological parameters, the correlation between CA15-3, CEA or TPS levels with overall survival, and their impact on prognosis. Results: First, at the univariate analysis, higher preoperative serum CA15-3 was significantly associated with older age of onset (≥45 years, P=0.049), and the expression of TPS was related with some traditional prognostic factors such as tumor size (P=0.030), histologic grade (P=0.001) and lymph node status (P=0.008). Second, overall survival were significantly shorter among patients with elevated preoperative serum CA15-3 (P=0.000) or TPS (P=0.038) respectively. Finally, multivariate Cox regression indicated that histological grading (P=0.028), estrogen receptor(ER) expression (P=0.001) and elevated preoperative values of CA 15-3 (P=0.015) were independent prognostic factors for overall survival. Conclusions: Our study demonstrates that higher expression of preoperative serum CA15-3 or TPS was closely correlated with clinicopathology and overall survival, and CA15-3 before treatment can be used as an independent prognostic parameter in patients with primarily breast cancer. However, serum CEA had poor correlation with clinical prognostic factors.

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Molecular Characterization of a Tissue‐Polypeptide‐Specific‐Antigen Epitope and its Relationship to Human Cytokeratin 18

Cited by 84 publications

References 21 publications

Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy

Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy

Cancer-associated Cleavage of Cytokeratin 8/18 Heterotypic Complexes Exposes a Neoepitope in Human Adenocarcinomas

Correlation of Preoperative Serum Tumor Markers with Clinicopathological Features and Prognosis in Breast Cancer

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