CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

Full Abstract

Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine-resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC-1 cells. Gemcitabine-resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere-forming activity than parental cells. After high-dose gemcitabine treatment to eliminate most of the cells, CD44(+) cells proliferated and reconstituted the population of resistant cells. CD44(+)CD24(+)ESA(+) cells remained as a small subset in the resistant cell population. Among ATP-binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose-dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44-positive tumors showed poor prognosis. These data indicate that cancer stem-like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer.

Author information

Author/s: Hong, Sung Pil (SP); Wen, Jing (J); Bang, Seungmin (S); Park, Seungwoo (S); Song, Si Young (SY);

Affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Nov; vol 125 (issue 10) : pp 2323-31

Dates: Created 2009/09/28; Completed 2009/11/05;

PMID: 19598259, status: MEDLINE (last retrieval date: 11/5/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adenocarcinoma - drug therapy; metabolism; pathology
Animals
Antigens, CD44 - metabolism
Antimetabolites, Antineoplastic - therapeutic use
Blotting, Western
Cell Line, Tumor
Colony-Forming Units Assay
Deoxycytidine - analogs & derivatives; therapeutic use
Drug Resistance, Neoplasm
Humans
Immunoenzyme Techniques

Associated Chemicals: ABCB1 protein, human (0) ; Antigens, CD44 (0) ; Antimetabolites, Antineoplastic (0) ; P-Glycoprotein (0) ; RNA, Messenger (0) ; RNA, Small Interfering (0) ; gemcitabine (103882-84-4) ; Deoxycytidine (951-77-9)

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