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Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma

Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma
Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma
Purpose: The purpose of this study was to determine the role of functional interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) in the formation of the desmoplastic reaction (DR) in pancreatic cancer and to characterize the effect of type I collagen (the predominant component of the DR) on pancreatic cancer cell phenotype.
Experimental Design: PSCs and type I collagen were identified in sections of pancreatic cancer using immunohistochemistry, and their anatomic relationship was studied. Interactions among pancreatic cancer cell lines (MIA PaCa-2, Panc-1, and AsPC-1), primary cultures of human PSCs, and type I collagen were investigated in a series of tissue culture models.
Results: In vivo, the DR causes gross distortion of normal pancreas, bringing cancer cells into close contact with numerous PSCs and abundant type I collagen. In tissue culture models of pancreatic cancer, conditioned media from each cell line increased PSC [3H]thymidine incorporation up to 6.3-fold that of controls, and AsPC-1 cells also increased PSC collagen synthesis 1.3-fold. Type I collagen was observed to increase long-term survival of pancreatic cancer cells treated with 5-fluorouracil, by up to 62% in clonogenic assays. This was because type I collagen increased the proliferation of cancer cells ([3H]thymidine incorporation was up to 2.8-fold that of cells cultured on tissue culture plastic) and reduced apoptosis of AsPC-1 cells in response to 5-fluorouracil (by regulating mcl-1).
Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.
1078-0432
7427-7437
Armstrong, Thomas
3b87df01-cd08-4048-91c4-7390c73a5960
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Murphy, Lindsay B.
fdd8d59c-cf8d-413c-a8c3-eb52acbbdac2
Bateman, Adrian C.
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Conti, John A.
4195688d-366b-4253-986b-9b3ca67598c9
Fine, David R.
ce3d6a77-040e-4aec-a8f5-4c4c22431605
Johnson, Colin D.
e50aa9cd-8c61-4fe3-a0b3-f51cc3a6c74a
Benyon, R.Christopher
09dfc448-03b1-43e3-90be-4135c3cd8516
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Armstrong, Thomas
3b87df01-cd08-4048-91c4-7390c73a5960
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Murphy, Lindsay B.
fdd8d59c-cf8d-413c-a8c3-eb52acbbdac2
Bateman, Adrian C.
28ae82e3-b93a-429a-81f5-04e8f1ff4cc7
Conti, John A.
4195688d-366b-4253-986b-9b3ca67598c9
Fine, David R.
ce3d6a77-040e-4aec-a8f5-4c4c22431605
Johnson, Colin D.
e50aa9cd-8c61-4fe3-a0b3-f51cc3a6c74a
Benyon, R.Christopher
09dfc448-03b1-43e3-90be-4135c3cd8516
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2

Armstrong, Thomas, Packham, Graham, Murphy, Lindsay B., Bateman, Adrian C., Conti, John A., Fine, David R., Johnson, Colin D., Benyon, R.Christopher and Iredale, John P. (2004) Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clinical Cancer Research, 10 (21), 7427-7437. (doi:10.1158/1078-0432.CCR-03-0825).

Record type: Article

Abstract

Purpose: The purpose of this study was to determine the role of functional interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) in the formation of the desmoplastic reaction (DR) in pancreatic cancer and to characterize the effect of type I collagen (the predominant component of the DR) on pancreatic cancer cell phenotype.
Experimental Design: PSCs and type I collagen were identified in sections of pancreatic cancer using immunohistochemistry, and their anatomic relationship was studied. Interactions among pancreatic cancer cell lines (MIA PaCa-2, Panc-1, and AsPC-1), primary cultures of human PSCs, and type I collagen were investigated in a series of tissue culture models.
Results: In vivo, the DR causes gross distortion of normal pancreas, bringing cancer cells into close contact with numerous PSCs and abundant type I collagen. In tissue culture models of pancreatic cancer, conditioned media from each cell line increased PSC [3H]thymidine incorporation up to 6.3-fold that of controls, and AsPC-1 cells also increased PSC collagen synthesis 1.3-fold. Type I collagen was observed to increase long-term survival of pancreatic cancer cells treated with 5-fluorouracil, by up to 62% in clonogenic assays. This was because type I collagen increased the proliferation of cancer cells ([3H]thymidine incorporation was up to 2.8-fold that of cells cultured on tissue culture plastic) and reduced apoptosis of AsPC-1 cells in response to 5-fluorouracil (by regulating mcl-1).
Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.

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Published date: 1 November 2004

Identifiers

Local EPrints ID: 26205
URI: https://eprints.soton.ac.uk/id/eprint/26205
ISSN: 1078-0432
PURE UUID: e02bcee3-51ea-4429-8bca-59a0eaa885fa
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 21 Apr 2006
Last modified: 15 Aug 2019 00:49

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