JUNE 2016|| 33The underlying cause for cancer development is a change to
genes that control cell division and cell growth. Evidence for an
association of infectious viruses and bacteria in chronic inlam-
matory diseases and cancer is rapidly increasing, and 17% of global
cancer is now attributed to infectious agents. For example, human
papillomavirus is responsible for cancers of the cervix and penis,
while liver cancer has been linked to both hepatitis B and C.
Certain bacteria have also been linked to cancer development.
Their capacity to induce chronic inlammation is believed to be
involved.
Perhaps the best-known example of bacterially induced cancer
involves Helicobacter pylori, a bacterium usually found in the
stomach. Inlammation of the stomach lining due to H. pylori
colonisation results in chronic gastritis. Stomach and duodenal
ulcers can result.
One way in which H. pyloriis thought to promote cancer is by
inducing chronic inlammatory stress, leading to the activation of
multiple cancer-causing pathways. The bacterium produces viru-
lence factors that induce genes encoding pro-inlammatory mole-
cules such as interleukin-6 (IL6). This creates a microenvironment
that facilitates the transformation of gastric epithelial cells to
cancerous cells.
So could the p37 protein on the surface of M. hyorhinisbe
involved in the development of cancer?
We found that when puriied p37 protein is added to ibro blast
cells it rapidly induced genes encoding three proteins involved in
inlammation and cancer metastasis.
- IL6 is involved in inlammatory diseases such as arthritis, and
can induce cell proliferation and invasion. - ANGPTL4 also plays an important role in inlammation,
cancer growth and metastasis. - SAA3 is implicated in several chronic inlammatory diseases,
including rheumatoid arthritis, and promotes metastasis.
Many of the genes activated by p37 are part of a signalling
cascade involving the STAT3 protein, which regulates the expres-
sion of speciic genes. STAT3 inhibitors are used therapeutically
for inlammatory disease and cancer.
However, when we added a STAT3 inhibitor to the cells, the
p37-induced expression of genes was signiicantly increased rather
than inhibited. The reasons for this are unclear, but recent reports
from other labs have also found an increased inlammatory response
with STAT3 inhibitors and led to a re-evaluation of their thera-
peutic use.
So how does the p37 protein activate the expression of genes
that are involved in inlammation and cancer progression?
We found that p37 binds to a receptor protein on the surface
of the ibroblast cells called TLR4, which recognises pathogens and
triggers the inlammatory response. Molecules that bind to TLR4
include certain viral proteins and lipopolysaccharides from Gram-
negative bacteria.
Activation of TLR4 by infectious agents can trigger numerous
signalling cascades, eliciting a strong inlammatory response. One
such cascade involves IL6. Elevated expression of TLR4 has been
reported in breast, colon, gastric, lung and ovarian cancers. Our
research found that the induction of gene expression in mouse
ibroblasts by p37 was signiicantly reduced when the TLR4
receptor was blocked.
The team from Peking University has also recently associated
p37–TLR4 withM. hyorhinis-infected human gastric cancer cells.
P37-induced expression of ANGPTL4 was only partly inhibited
when we blocked the TLR4 receptor, so an additional receptor
may play a role in its activation.
How might the induction of pro-inlammatory and cancer-
related pathways by p37 in ibroblast cells relate to cancer devel-
opment? Do the ibroblasts eventually develop into tumour cells
when infected byM. hyorhinis?
We don’t know. However, we do know that cancer-associ-
ated ibroblasts support tumour growth, development, invasion
and metastasis via the release of molecules that facilitate inlam-
mation and the formation of blood vessels. In this contextM.
hyorhinisinfection could play an important role in cancer progres-
sion.
Further research is required to answer a number of important
questions that may further strengthen the connection between
infection withM. hyorhinisand cancers.- Do ibroblasts and other cell types eventually develop into
tumour cells when infected byM. hyorhinis? - CouldM. hyorhinisinfection participate in the development
of human inlammatory diseases such as arthritis? - Do other mycoplasma species induce similar responses to those
induced byM. hyorhinis? Since other mycoplasma species also
possess p37 equivalents, are these proteins also capable of
inducing genes involved in inlammation and cancer? If not,
why not? - What is the second cell surface receptor bound by p37 that
participates in the activation of ANGPTL4?
Evidence is growing that certain viruses and bacteria could
increase the risk of cancer by promoting general inlammation. As
a consequence, other key cellular processes would be affected.
Our studies have identiied a mechanism, namely the p37 protein,
by which a mycoplasma infection can rapidly and strongly induce
pro-inlammatory and cancer-related genes.
Amber Gomersall is a PhD graduate of La Trobe University’s Department of Animal, Plant and
Soil Sciences, where Roger Parish is an Emeritus Professor.
Certain bacteria have also been linked
to cancer development. Their capacity
to induce chronic inflammation is
believed to be involved.