Laboratory experiments have previously shown that cancer cells
overproduce an enzyme, heparanase, which splits the body�s own
polysaccharide heparan sulfate into shorter fragments. The amount of
enzyme is related to the degree of malignancy. A
study was published in the journal Nature
Chemical Biology in which Uppsala University researchers show, on the
basis of animal models, that an inhibitor for heparanase would be
extremely interesting as a drug candidate.
Heparan sulfate is a polysaccharide, that is, a chain of linked sugar
units, with sulfate groups in different positions. These chains are
found on the surface of practically every cell in the body. The
sulfate groups enable binding to a number of proteins, such as
inflammation proteins and growth factors. Heparan sulfate can thereby
regulate different processes in the body, during embryonic development,
for example, but also in various conditions of sickness. The capacity
for protein-binding generally increases the more sulfate groups there
are on the polysaccharide.
The enzyme heparanase splits heparan sulfate at certain points and
converts the long chains into shorter fragments. Research at other
laboratories has shown that cancer cells in many cases overproduce
heparanase and that the amount of heparanase correlates with the
degree of malignancy of the cancer cells and their capacity to
metasthesize. The connection is believed to have multiple explanations.
Heparanase helps cancer cells make their way through tissue barriers,
but it also stimulates the heightened generation of blood vessels that
is necessary for tumor growth. The fragments function as carriers of
growth factors that can promote tumor growth in many ways.
In the current project the scientists introduced the gene for human
heparanase into a mouse, so that the enzyme would be overproduced in
several organs. Besides the expected splitting of heparan sulfate,
they found that the metabolism of the polysaccharide was stimulated,
but that the number of sulfate groups increased at the same time. The
�high-sulfated� fragments released by the enzyme evince dramatically
increased binding to certain growth factors of potential importance to
tumor growth. When they examined heparan sulfate from authentic cancer
cells instead, or from cancer tissue that had overproduced heparanase,
it was found that here too there was an increase in the number of
sulfate groups compared with heparan sulfate from corresponding normal
cells/tissues. The findings indicate that producing an inhibitor for
heparanase is an urgent step in discovering new drugs for cancer.
Further Information and Source:
-
Martha L Escobar Galvis, Juan Jia, Xiao Zhang, Nadja Jastrebova,
Dorothe Spillmann, Eva Gottfridsson, Toin H van Kuppevelt, Eyal
Zcharia, Israel Vlodavsky, Ulf Lindahl & Jin-Ping Li: Transgenic or tumor-induced expression of heparanase upregulates
sulfation of heparan sulfate.
In: Nature Chemical Biology;
published online: 21 October 2007; doi: 10.1038/nchembio.2007.41