Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients

Ausch, Christoph; Buxhofer‐Ausch, Veronika; Olszewski, Ulrike; Hinterberger, W; Ogris, E; Schiessel, R; Hamilton, G.

doi:10.1016/j.ejso.2009.02.007

Cited by 47 publications

(34 citation statements)

References 17 publications

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“…The first studied pre-and post-operative serum levels of CK18 -Asp396 in 31 patients (Ausch et al, 2009). It also assessed serum levels of CK18 -Asp396 in 10 patients receiving combination chemotherapy with oxaliplatin/capecitabine.…”

Section: Discussionmentioning

confidence: 99%

Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response

et al. 2009

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BACKGROUND: Plasma biomarkers may be particularly useful as a predictor or early marker of clinical response to treatment in addition to radiological imaging. Cytokeratin 18 (CK18) is an epithelial-specific cytokeratin that undergoes cleavage by caspases during apoptosis. Measurement of caspase-cleaved (CK18 -Asp396) or total cytokeratin 18 (CK18) from epithelial-derived tumours could be a simple, non-invasive way to monitor or predict responses to treatment. METHODS: Soluble plasma CK18 -Asp396 and CK18 were measured by ELISA from 73 patients with advanced gastrointestinal adenocarcinomas before treatment and during chemotherapy, as well as 100 healthy volunteers. RESULTS: Both CK18 -Asp396 and total CK18 plasma levels were significantly higher in patients compared with the healthy volunteers (P ¼ 0.015, Po0.001). The total CK18 baseline plasma levels before treatment were significantly higher (P ¼ 0.009) in patients who develop progressive disease than those who achieve partial response or stable disease and this correlation was confirmed in an independent validation set. The peak plasma levels of CK18 occurring in any cycle following treatment were also found to be associated with tumour response, but peak levels of CK18 -Asp396 did not reach significance (P ¼ 0.01, and P ¼ 0.07, respectively). CONCLUSION: Plasma levels CK18 are a potential marker of tumour response in patients with advanced gastrointestinal malignancy.

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Section: Discussionmentioning

confidence: 99%

Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response

et al. 2009

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“…Early studies suggest that these assays may have important clinical biomarker utility, as increased levels of circulating CK18 may be prognostic and/or predict tumour response to chemotherapy in a number of different solid tumours (Steele et al, 2008;Scott et al, 2009). Studies on specific tumour types include lung (Ulukaya et al, 2007;Hou et al, 2009), breast (Olofsson et al, 2007), prostate (Kramer et al, 2006), head and neck (Ozturk et al, 2009), colorectal (Ausch et al, 2009;Koelink et al, 2009) and testicular (de Haas et al, 2008) tumours. Although a recent study concluded that plasma levels of CK18 are a potential marker of tumour response in patients with advanced gastrointestinal malignancy (Scott et al, 2009) no previous studies have been reported in patients with pancreatic cancer.…”

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confidence: 99%

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer

et al. 2010

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BACKGROUND: Enzyme-linked immunoassays of full-length (M65) and/or caspase-cleaved (M30) cytokeratin 18 (CK18) released from epithelial cells undergoing necrosis and/or apoptosis, respectively, may have prognostic or predictive biomarker utility in a range of solid tumour types. Characterisation of baseline levels of circulating full length and cleaved CK18 specifically in patients with pancreatic cancer. METHODS: Plasma samples from 103 patients with pancreatic cancer stored at À80 1C were assayed for M65 and M30 levels. The median (inter-quartile range (IQR)) duration of plasma storage was 34 (23 -57) months. Patients with metastatic disease (n ¼ 19) were found to have greater median (IQR) M65 levels (1145 (739 -1698) U l À1 ) compared with the locally advanced (n ¼ 20; 748 (406 -1150) U l À1 ) and resected (n ¼ 64; 612 (331 -987) U l À1 ) patients (P ¼ 0.002). Elevated M65 levels were associated with poorer overall survival on univariate (Po0.001) but not multivariate (P ¼ 0.202) analysis. M65 concentrations also exhibited significant associations with concurrent serum -bilirubin levels (Po0.001) and the duration of plasma storage (Po0.001). CONCLUSIONS: Baseline plasma CK18 levels in pancreatic cancer are affected by the presence of obstructive jaundice and prolonged plasma storage. Clinical biomarker studies utilising serial CK18 levels are warranted in pancreatic cancer, provided consideration is given to these potentially confounding factors. Pancreatic ductal adenocarcinoma is a leading cause of cancer deaths (http://www-dep.iarc.fr/) wherein, because of its characteristically late presentation, only 10 -15% of patients present with resectable tumours (Alexakis et al, 2004). For the remaining 85 -90% of patients presenting with inoperable disease, administration of systemic chemotherapy represents the most widely utilised palliative treatment modality (Yip et al, 2006). Conventional chemotherapy regimens incorporating either 5-FU or gemcitabine typically result in only modest improvement in overall survival (Sultana et al, 2007). One of the key challenges in accelerating improved cancer therapeutics is the identification of biomarkers to enable early objective assessment of tumour responses to chemotherapy (Kummar et al, 2007).Necrosis of malignant and normal epithelial cells cause release of cytokeratin 18 (CK18) (Kramer et al, 2004), a type I intermediate filament protein and a component of the intracellular cytoskeleton (Fuchs and Weber, 1994). Caspase-mediated cleavage of the CK18 contributes to the degradation of the intracellular cytoskeleton if epithelial cells undergo apoptosis (Leers et al, 1999). Enzymelinked immunosorbent assays (ELISAs) have been developed to measure circulating concentrations of both full-length CK18 (M65) and caspase-cleaved CK18 fragments (M30) (Kramer et al, 2004). Thus, the M65 ELISA reports necrotic and apoptotic epithelial cell death, whereas the M30 ELISA reports levels of epithelial apoptosis specifically (Kramer et al, 2004). Early studies suggest that these assays ...

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“…The group with increased postoperative levels of M65 was characterized by a higher incidence of BM-DTCs in comparison to patients with postoperatively normalizing M65. In the case of circulating ccCK18 almost 80% of patients exhibited a significant decrease of approximately 75% in response to tumor removal; however, the remaining 20% revealed a mean increase of 40% of these CK fragment levels postoperatively (Ausch, et al, 2009b). The frequency of BM-DTCs, as detected before surgery with help of the pan-CK antibody A45-B/B3, was not significantly different for these two groups of patients with normalizing and increased ccCK18 levels.…”

Section: Effect Of Radical Tumor Surgery On Circulating Ck18 Fragmentmentioning

confidence: 84%

Cytokeratin 18 (CK18) and CK18 Fragments for Detection of Minimal Residual Disease in Colon Cancer Patients

Olszewski-Hamilton¹,

Buxhofer-Ausch²,

Hamilton³

2012

Cytokeratins - Tools in Oncology

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Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients

Cited by 47 publications

References 17 publications

Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response

Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer

Cytokeratin 18 (CK18) and CK18 Fragments for Detection of Minimal Residual Disease in Colon Cancer Patients

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