Source: University
of California - San Diego
Summary: Compared to
chimpanzees, our closest evolutionary cousins, humans are particularly prone to
developing advanced carcinomas -- the type of tumors that include prostate,
breast, lung and colorectal cancers -- even in the absence of known risk
factors, such as genetic predisposition or tobacco use. A recent study helps
explain why.
Compared to
chimpanzees, our closest evolutionary cousins, humans are particularly prone to
developing advanced carcinomas -- the type of tumors that include prostate,
breast, lung and colorectal cancers -- even in the absence of known risk
factors, such as genetic predisposition or tobacco use.
A recent
study led by researchers at University of California San Diego School of
Medicine and Moores Cancer Center helps explain why. The study, published
December 9, 2020 in FASEB BioAdvances, suggests that an
evolutionary genetic mutation unique to humans may be at least partly to blame.
"At
some point during human evolution, the SIGLEC12 gene -- and more specifically,
the Siglec-12 protein it produces as part of the immune system -- suffered a
mutation that eliminated its ability to distinguish between 'self' and invading
microbes, so the body needed to get rid of it," said senior author Ajit
Varki, MD, Distinguished Professor at UC San Diego School of Medicine and Moores
Cancer Center. "But it's not completely gone from the population -- it
appears that this dysfunctional form of the Siglec-12 protein went rogue and
has now become a liability for the minority of people who still produce
it."
Ajit Varki,
who is also co-director of both the Glycobiology Research and Training Center
and Center for Academic Research and Training in Anthropogeny, led the study
with Nissi Varki, MD, professor of pathology at UC San Diego School of
Medicine.
In a study
of normal and cancerous tissue samples, the researchers discovered that the
approximately 30 percent of people who still produce Siglec-12 proteins are at
more than twice the risk of developing an advanced cancer during their
lifetimes, compared to people who cannot produce Siglec-12.
Normally,
genes that encode such dysfunctional proteins are eliminated by the body over
time, and approximately two-thirds of the global human population has stopped
producing the Siglec-12 protein. Where the gene still hangs around in humans,
it was long thought be of no functional relevance, and there have been very few
follow-up studies over the two decades since it was discovered. Meanwhile,
chimpanzees still produce functioning Siglec-12.
When Nissi
Varki's team set out to detect the Siglec-12 in non-cancerous tissue samples
using an antibody against the protein, approximately 30 percent of the samples
were positive, as expected from the genetic information. In contrast, the
majority of advanced cancer samples from the same populations were positive for
the Siglec-12 protein.
Looking at a
different population of patients with advanced stage colorectal cancer, the
researchers found that more than 80 percent had the functional form of the
SIGLEC-12 gene, and those patients had a worse outcome than the minority of
patients without it.
"These
results suggest that the minority of individuals who can still make the protein
are at much greater risk of having an advanced cancer," Nissi Varki said.
The
researchers also validated their findings in mice by introducing tumor cells
engineered to produce Siglec-12. The resulting cancers grew much faster, and
turned on many biological pathways known to be involved in advanced cancers,
compared to control tumor cells without functioning Siglec-12.
According to
Ajit Varki, this information is important because it could be leveraged for
future diagnostics and treatments. The team got a jump start by developing a
simple urine test that could be used to detect the presence of the
dysfunctional protein, and "we might also be able to use antibodies
against Siglec-12 to selectively deliver chemotherapies to tumor cells that
carry the dysfunctional protein, without harming non-cancerous cells," he
said.
Additional
co-authors of the study include: Shoib S. Siddiqui, Michael Vaill, Raymond Do,
Naazneen Khan, Andrea L. Verhagen, Gen-Sheng Feng, UC San Diego; Wu Zhang,
Heinz-Josef Lenz, University of Southern California; Teresa L. Johnson-Pais,
Robin J. Leach, University of Texas Health Science Center; and Gary Fraser,
Charles Wang, Loma Linda University.
Funding for
this research came, in part, from the National Institutes of Health (grants
R01GM32373, 5U01CA086402, T32GM008666 and DK007202).
Disclosure: Professor Ajit Varki is a scientific advisor to Mablytics Inc., a biotech startup which is developing immunotherapeutics directed against this novel Siglec target in solid tumors. Mablytics has also funded a related research collaboration with UC San Diego led by Nissi Varki.
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