TY - JOUR
T1 - Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility
AU - Clausen, Thomas Mandel
AU - Pereira, Marina Ayres
AU - Nakouzi, Nader Al
AU - Oo, Htoo Zarni
AU - Agerbæk, Mette
AU - Lee, Sherry
AU - Ørum-Madsen, Maj Sofie
AU - Kristensen, Anders Riis
AU - El-Naggar, Amal
AU - Grandgenett, Paul M.
AU - Grem, Jean L.
AU - Hollingsworth, Michael A.
AU - Holst, Peter J.
AU - Theander, Thor
AU - Sorensen, Poul H.
AU - Daugaard, Mads
AU - Salanti, Ali
N1 - Funding Information:
The authors would like to thank Birita Kjærbæk and Elham Alijazaeri for their technical assistance in the above-mentioned experiments. T.M. Clausen, M.A. Pereira, M.Ø. Agerbæk, P.J. Holst, T. Theander, M. Daugaard, and A. Salanti were funded by the European Research Council (ERC) and the US Department of Defense (DoD). T.M. Clausen, N.A. Nakouzi, H.Z. Oo, S. Lee, and M. Daugaard were funded by Prostate Cancer Canada funded by Canada Safeway (Grant # RS2014-02). P.M. Grandgenett, J.L. Grem, and M.A. Hollingsworth were funded by SPORE in Pancreatic Cancer (Rapid Autopsy Pancreas program), CA127297, TMEN Tumor Microenvironment Network, U54 CA163120, and NCI Cancer Center Support GrantP30 CA36727. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.
AB - Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.
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U2 - 10.1158/1541-7786.MCR-16-0103
DO - 10.1158/1541-7786.MCR-16-0103
M3 - Article
C2 - 27655130
AN - SCOPUS:85003869006
VL - 14
SP - 1288
EP - 1299
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 12
ER -