Ikuo Saiki
Research Institute for Wakan-yaku, Toyamo Medical and Pharmaceutical
University, Toyama 930-01, Japan
Abstract: The adhesive interaction between tumor cells and host
cells or the extracellular matrix plays a crucial role in metastasis formation.
Therefore, understanding the mechanism controlling metastasis may assist
in the development of antimetastatic therapy. We have used synthetic or
recombinant polypeptide analogues containing the Arg-Gly-Asp (RGD) sequence
found in the functional domains of fibronectin, such as poly(RGD) or CH-271,
to regulate the mechanisms involved in cell adhesion during the metastatic
process. Poly(RGD) inhibited experimental lung and liver metastasis effectively
when coinjected i.v. with various types of tumors. In a model of spontaneous
lung metastasis using the B16-BL6 melanoma, repeated administration of this
polypeptide before or after surgical excision of the primary tumor resulted
in a significant inhibition of tumor metastasis without affecting the growth
of the primary tumor and substantially prolonged the survival time of mice.
The mechanism responsible for the inhibition of tumor metastasis by the
polypeptides is at least partly associated with the ability to interfere
with cellular functions such as adhesiveness, motility and invasiveness
in the process of metastasis. Combined treatment of the CH-271 fusion polypeptide
and anticancer drugs, i.e., anti-adhesion therapy combined with chemotherapy,
caused a marked inhibition of lung and liver metastasis of tumors as compared
with either treatment alone or with the control. In contrast, the promotion
of tumor cell interaction with immune cells via cell adhesion molecules,
which differs from the anti-adhesive mechanism, may lead to the induction
of anti-tumor immune responses and, consequently, to the inhibition of tumor
metastasis. The transfection of the gene of the B7-1 adhesion molecule into
tumor cells (B16-BL6 or K1735-M2 melanoma) resulted in the remarkable reduction
of lung metastasis caused by the i.v. injection into mice. Immunization
of B7-transfected tumor was effective as a tumor vaccine for preventing
the metastasis of B7 negative original tumor cells. Thus, the regulation
of the adhesive interaction with tumor cells may provide a new and promising
approach for the control and prevention of cancer metastasis.
Keywords: Cell adhesion, Metastasis, Invasion, Fibronectin, Arg-Gly-Asp
(RGD)