Abstract 3164: Cancer cell adhesion and degradome interact to metastasize
Authors: Rizwan Asif , Cheng Menglin , Krishnamachary Balaji , Jiang Lu , Bhujwalla Zaver , Kristine Glunde 
Published: May 2015

Background: Adhesion molecules of cancer cells interact with the cancer cell degradome. This is evident from (i) co-localized expression of adhesion molecules such as integrins and degradative enzymes such matrix metalloproteases (MMPs), (ii) regulation of degradome activity by integrin signaling, (iii) key integrins and MMPs binding to the same extracellular matrix (ECM) components, and (iv) interaction between integrins and membrane-bound MMPs in cell-ECM communication in several types of cancer (1-8). Integrins and the degradome have both been implicated in breast cancer metastasis. We are testing for the first time the hypothesis that it is the interactome between these two molecular networks that is critical for breast tumor metastasis to occur.

Experimental Design: We performed comparative studies with a panel of non-metastatic (BT-474, T47D, MCF7, SKBr3) versus metastatic (MDA-MB-231, SUM149, SUM159, MDA-MB-468) human breast cancer cell lines and xenografts. All cell lines stably expressed tdTomato fluorescent protein for optical tracking. Comparative immunoblotting, zymography, migration and invasion assays were performed. Enzymatically activatable optical imaging probes IntegriSense (integrins), MMPSense (MMP), and Angiosense (blood vessels) from PerkinElmer were used in our in vivo imaging studies. Primary tumor sizes of 200 mm3 and 600 mm3 were used to account for different stages of tumors growth.

Results: Analysis of 1,144 genes from a panel of 28 human breast cancer cell lines from publicly available data bases (9) showed that metastatic breast cancer cells have significantly (p&lt;0.01) higher levels of cell adhesion (integrin α-1,4,5,6,v, integrin β-1, CD44) and ECM degrading enzymes (MMP-2,3,11,14,16,19). Metastatic human breast cancer cell lines expressed elevated protein levels of MMP-1 and MMP-14 compared to nonmetastatic lines. Zymography demonstrated that metastatic breast cancer cells secreted increased amounts of active MMP-2 and MMP-9 compared to non-metastatic cell lines. Metastatic tumor xenografts displayed significantly higher combined MMP-1,-2,-3,-9,-13 activity along with increased integrin expression compared to non-metastatic tumors in vivo.

Conclusion: Our results show that elevated activity and expression levels of integrins and MMPs coincide in metastatic breast cancer cell lines and xenografts, which indicates that they may cooperate and interact to enable cancer cell escape from the primary tumor and metastasis. We will perform additional studies to further test our hypothesis by combining cancer cell and tumor studies.

References: 1. Knoblauch et al, FASEB J 2007. 2. Friedl et al, Nat Rev Cancer 2003. 3. Birkedal et al, Biol Med 1993. 4. Deryugina et al, Exp Cell Res 2001. 5. Brooks et al, Cell 1996. 6. Mitchell et al, Cancer Res 2010. 7. Gonzalo et al, Biofactors 2008. 8. Chapman et al, Thromb Haemost 2001. 9. Hollestelle et al, Cancer Res Treat 2009.

Citation Format: Asif Rizwan, Menglin Cheng, Balaji Krishnamachary, Lu Jiang, Zaver Bhujwalla, Glunde Kristine. Cancer cell adhesion and degradome interact to metastasize. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3164. doi:10.1158/1538-7445.AM2014-3164