DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells.

Ivanovska, Jelena; Zlobec, Inti; Forster, Stefan; Karamitopoulou, Evanthia; Dawson, Heather; Kölzer, Viktor; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; Rau, Tilman; Schneider-Stock, Regine (2015). DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells. OncoTarget, 6(34), pp. 36774-36788. Impact Journals LLC 10.18632/oncotarget.4908

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Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Zlobec, Inti; Karamitopoulou, Evanthia; Dawson, Heather; Kölzer, Viktor; Lugli, Alessandro and Rau, Tilman

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

29 Oct 2015 11:22

Last Modified:

01 Feb 2018 15:09

Publisher DOI:

10.18632/oncotarget.4908

Related URLs:

PubMed ID:

26405175

BORIS DOI:

10.7892/boris.72356

URI:

https://boris.unibe.ch/id/eprint/72356

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