Decoy protein shows promise as potential cancer therapy

July 19, 2004

Two research studies published in the July issue of Cancer Cell demonstrate that targeting a portion of a protein associated with many human cancers, including breast, lung, liver, kidney, and colorectal cancers, may have significant potential therapeutic applications with less toxicity than more general inhibitors of the same signaling pathway.

Fundamental processes like cell proliferation, migration, differentiation, and survival are regulated in part by hepatocyte growth factor (HGF). HGF controls and coordinates many events that are critical for embryonic development and for adult wound healing and tissue regeneration. However, in addition to playing a necessary role in these essential normal processes, HGF signaling through its receptor Met is usurped by many tumors to promote growth, survival, and metastases.

Dr. Paolo Michieli and colleagues from the University of Torino Medical School in Italy examined whether targeted inhibition of HGF/Met signaling may be an effective anticancer therapeutic. The researchers engineered a truncated version of the Met receptor that consisted only of the receptor's extracellular domain. This version of Met, called decoy Met, was soluble and could be systemically introduced into mice. Decoy Met inhibited the growth and survival of a variety of human tumor cells that were grafted into mice, interfered with the ability of the tumors to establish a blood supply, and prevented the tumor cells from spreading. Importantly, decoy Met did not interfere with normal physiological functions in adult mice. The authors suggest that the extracellular portion of the receptor present in decoy Met successfully competes for HGF binding and may be a promising therapeutic agent.

A second study by Dr. Dineli Wickramasinghe and colleagues from the Department of Molecular Oncology at Genentech in San Francisco examined a very specific part of the extracellular domain of the Met receptor, called the Sema domain. The Met Sema domain was required for HGF-stimulated Met activation in tumor cells. In addition, the Met receptor dimerization, a process that is necessary for full activation of Met and therefore activation of signaling molecules downstream of Met, only occurred when the Sema domain was intact. This is significant because hyperactivation of the Met receptor, even in the absence of HGF, is common in many types of cancer.

When the Sema domain by itself was introduced into Met-overexpressing tumor cells, it blocked receptor activation and downstream signals that stimulate cell motility and migration. According to Dr. Wickramasinghe, "These observations point to the exciting prospect of treating Met-overexpressing tumors not only by targeting the Sema domain of Met but also by utilizing the Sema domain itself as a biotherapeutic."
P. Michieli, M. Mazzone, C. Basilico, S. Cavassa, A. Sottile, L. Naldini, and P.M. Comoglio: "Targeting the tumor and its microenvironment by a dual-function decoy Met receptor"

M. Kong-Beltran, J. Stamos, and D. Wickramasinghe: "The Sema domain of Met is necessary for receptor dimerization and activation"

Related Preview by Y.-W. Zhang, C. Graveel, N. Shinomiya, and G.F. Vande Woude: "Met decoys: Will cancer take the bait?"

Publishing in Cancer Cell, Volume 6, Number 1, July 2004.

Cell Press

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