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D. Gullberg
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-095 - Integrin a11b1 Regulates Cancer Stromal Stiffness and Promotes Tumorigenicity and Metastasis in Non-Small Cell Lung Cancer (ID 3084)
09:30 - 17:00 | Author(s): D. Gullberg
- Abstract
Background:
Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is over-expressed in carcinoma-associated fibroblasts (CAFs) in non- small cell lung cancer (NSCLC). We have studied the direct role of stromal integrin a11 on the growth and metastasis of NSCLC cells using novel immune-compromised a11 deficient mice.
Methods:
We developed α11 non-expressing immune-deficient mice by back-crossing for at least 10 times the α11-deficient heterozygous C57BL/6J mice (+/-) to obtain a homogenous C57BL/6 background. These were subsequently bred with the BALB/c SCID mice for 7 generations, producing α11-deficient heterozygous (+/-) in SCID background. In vivo studies were done using subcutaneous tumorigenicity assay and orthotopic model to evaluate metastatic potential of integrin α11. Immunostaining were carried out using integrin α11, α-SMA, and cytokeratin. PisroSirius red staining was used to visualize the collagen fibers. Images were taken by polarized-light microscopy using parallel and perpendicular polarizer orientations on an Olympus BX51 microscope. Second Harmonic Generation (SHG) was used to visualize fibrillar collagen and atomic force microscopy was applied to measure the stiffness in tumor stroma.
Results:
The tumor growth of both primary human lung cancer (PHLC) and established NSCLC cells in α11 knockout (α11[-/-]) mice was significantly impeded compared to wild type (α11[+/+]). Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11[-/-] and α11[+/+] mice showed significant reduction in the metastatic potential of these cells in the α11[-/-] mice. Using mouse WG-6v2 Illumina Bead Chips, we identified that alpha11 expression correlates with that of a fibrillar collagen cross-linking enzyme, LOXL1, in the xenograft stroma. Fibrillar collagen was highly disorganized and had a significantly lower elastic modulus in the alpha11 knockout xenografts compared to wildtype. The results suggest a role for α11 in promoting tumor growth and metastatic progression by affecting the collagen stiffness of the tumor stroma.
Conclusion:
The integrin a11β1 signaling pathway in CAFs promotes tumor growth and metastasis of NSCLC cells. This appears closely linked to collagen cross-linking, the organization, and stiffness of fibrillar collagen matrices.
