cancers
Newly identified toxin common in E. coli bacteria accelerated colon
cancer in study mice; confirming link to human colorectal cancers could pave way for developing preventive drugs

Date:
January 12, 2022
Source:
Johns Hopkins University Bloomberg School of Public Health
Summary:
The discovery raises the possibility that some of the roughly two
million new cases of colorectal cancer every year around the world
originate from brief and seemingly mild food-poisoning events.



FULL STORY ========================================================================== Strains of bacteria that cause common food-poisoning symptoms often
contain a toxin that can damage DNA in intestinal cells, potentially
triggering colon cancer, according to a study from researchers at the
Johns Hopkins Bloomberg School of Public Health.


==========================================================================
The discovery raises the possibility that some of the roughly two million
new cases of colorectal cancer every year around the world originate
from brief and seemingly mild food-poisoning events. It also points
to the possibility of future drugs that prevent colorectal cancers by neutralizing the newly identified toxin, UshA.

The findings were published January 12 in the January edition of Cancer Discovery.

Prior research has suggested that certain bacteria that reside in the
gut can trigger colorectal cancer via persistent infections involving
chronic gut inflammation. Short-term infections causing food poisoning, including traveler's diarrhea, which normally resolve in a day or two,
have traditionally been considered non-carcinogenic.

"We hope this study will motivate other researchers to do epidemiological studies to investigate this potential link between transient diarrheal infections and colon cancer development," says study senior author
Fengyi Wan, PhD, associate professor in the Department of Biochemistry
and Molecular Biology at the Bloomberg School.

In the study, Wan's team performed experiments with a mouse model of
transient bacterial diarrheal disease using the bacterium Citrobacter rodentium,which has strong similarities to diarrhea-causing strains of
the human-infecting microbe Escherichia coli. The researchers observed
that Citrobacter infection quickly led to strong signs of DNA damage in gut-lining cells in the mice.



==========================================================================
The scientists also noted that the damage was dependent on a mechanism
in the bacteria called the Type 3 Secretion System. This syringe-like
appendage is used by some bacteria, including Citrobacter and
diarrhea-causing strains of E.

coli, to inject proteins into host cells. This mechanism facilitates
the invading microbes' growth and survival.

The researchers eventually zeroed in on a T3SS-injected protein, UshA,
that accounts for the DNA damage. They found that UshA, which can also
be produced by diarrhea-causing E. coli, contains a short segment with DNA-breaking enzyme activity.

The function of this DNA-breaking element in the life cycle of Citrobacter
is still unclear. (In the study, deleting it didn't seem to impair
bacterial growth or survival.) But the researchers found evidence in
their mouse study that UshA can have a definite cancer-causing effect
on the infected host.

The scientists experimented with a genetically engineered line of mice
that spontaneously develop colon tumors, and found that infecting these
mice with UshA-containing Citrobacter dramatically accelerated tumor development. By contrast, infection with an engineered Citrobacter
that lacks the UshA gene had essentially no effect in accelerating
tumor development.

The researchers also found that the types of mutations in the Citrobacter- accelerated colon tumors were highly similar to those that have been
catalogued in human colon tumors, again underscoring the potential
relevance to human health.



==========================================================================
A strong confirmation of this relevance won't be easy to accomplish,
Wan says, since transient infections by definition would be long gone
by the time tumors develop. (Colon tumors typically develop for many
years before they are detected.) Wan suggests that establishing a link
between UshA-containing microbes and human colorectal cancers will
require epidemiological studies.

These, he says, might best be done in sub-Saharan Africa, where diarrhea- causing bacterial infections -- and colorectal cancers -- are relatively common.

Wan is also now working with collaborating researchers to develop
inhibitors of the UshA toxin.

"In principle, you could give such inhibitors to patients who present
with diarrheal disease to protect them from cancer-promoting DNA damage,"
he says.

"Bacterial genotoxin accelerates transient infection-driven murine colon tumorigenesis" was co-authored by Yue Liu, Kai Fu, Eric Wier, Yifan Lei,
Andrea Hodgson, Dongqing Xu, Xue Xia, Dandan Zheng, Hua Ding, Cynthia
Sears, Jian Yang, and Fengyi Wan.

This work was supported in part by the National Institutes of Health (R01GM111682, R01CA244350, R21AI137719, T32CA009110), the American
Heart Association (19PRE34380234), the American Cancer Society (RSG-13-052-01-MPC), the U.S. Department of Defense (W81XWH-19-1-0479),
the Willowcroft Foundation, and the Graham Memorial Trust.

========================================================================== Story Source: Materials provided by Johns_Hopkins_University_Bloomberg_School_of_Public Health. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yue Liu, Kai Fu, Eric M. Wier, Yifan Lei, Andrea Hodgson,
Dongqing Xu,
Xue Xia, Dandan Zheng, Hua Ding, Cynthia L. Sears, Jian Yang,
Fengyi Wan.

Bacterial Genotoxin Accelerates Transient Infection-Driven Murine
Colon Tumorigenesis. Cancer Discovery, 2022; 12 (1): 236 DOI:
10.1158/2159- 8290.CD-21-0912 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112121515.htm
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