1 article in Nature + 1 Cell sub-journal reveals that tumor bacteria help tumor progression and resistance to treatment

In two new studies, researchers from Fred Hutchinson Cancer Center in the United States have revealed how bacteria invade tumors and may help tumors progress and spread
.
They also noted that different microbes in the tumor microbiome may influence how cancer responds to
treatment.
The findings also suggest a link between oral health and cancer, as microbes in the mouth are linked
to cancer in other parts of the body.

The two new studies focused on an oral bacterium called Fusobacterium
nucleatum, which has been linked to colorectal cancer.
The first study was published online on November 16, 2022 in the journal Nature as "Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer
.
" 。 The second study, published in the November 15, 2022 issue of Cell Reports, titled "The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota.
" ”
。

The tumor is often helped
in its efforts to survive and grow.
Non-cancerous cells surrounding the tumor can help it avoid attacks by the immune system, resist therapies that target them, and allow it to spread to other parts of
the body.
Scientists have now discovered that some of these neighbors who help tumors are not even human cells--- they are bacteria
.

Dr.
Susan Bullman, a cancer microbiome researcher at Fred Hutchinson Cancer Center and co-corresponding author of the two studies, said of the first study, "What we showed is that in some areas of the tumor, --- micro-niche regions, there is a large number of bacterial colonizations that are functionally different
from areas without bacteria.
These bacteria-rich regions have greater metastasis potential
.
”

Bullman and her collaborator, Christopher D.
Johnston, Ph.
D.
, a molecular microbiologist at Fred Hutchinson Cancer Center, combined observations from tumors with laboratory-based experiments and small molecule drug screenings to show that Fusobacterium nucleatum may shape the environment in tumors, shield it from immune attack and help it spread
in the body.
They found that some cancer treatments may be effective because they target not only tumor cells, but also the bacteria
that help them.

The authors also found that other microbes--- including the gut bacterium E.
coli--- may invalidate chemotherapy drugs with antimicrobial effects, which can leave both tumors and Fusobacterium nucleatus immune to treatment
.
The findings may help scientists develop new strategies to treat or target cancer itself
by targeting the cancer's microbiome.

Bullman, "These research efforts are at the intersection of cancer and microbiome research
.
There are compelling new data showing that almost all major cancer types have an intratumoral microbiome
.
”

In colorectal cancer, the association with bacteria may seem logical, but breast, pancreatic, and lung cancers are other cancers that have been shown to have microbial communities, and studies have shown that tumor microbiomes may shape cancer development, progression, and response
to treatment.

The authors refined a cutting-edge technique that allowed them to detect where genes are turned on and off in tumor tissue sections (spatial transcriptomics) and found that a range of bacterial species live in oral and colorectal cancers, but they are not evenly distributed
.

Johnston said, "We observed bacterial hotspots, the micro-niche region, which raises many questions
about how these bacterial hotspots form and may affect cancer biology.
" ”

Tumor regions where bacterial colonization is present are highly immunosuppressive, with fewer cancer-killing T cells
compared to other tumor regions.
Upregulated expression of immune checkpoint proteins also exists in tumor regions near the bacteria with T cells, which limit the cancer-killing effect
of T cells.
Some immune checkpoint inhibitors are approved to treat colorectal cancer, and the two new studies may help explain how a patient's tumor microbiota affects whether the cancer they have responded to immune checkpoint inhibitors
.

Specific findings from these two new studies:

(1) Tumor areas with bacteria are more likely to be necrotic and have fewer dividing cells
.
Ironically, according to other studies, this may be related to metastasis, as cells fall off and move to distant parts
of the body.

(2) In the lab, the authors cultured colorectal cancer spheroids (i.
e.
, tumor cells that grow in three-dimensional clusters) with immune cells called neutrophils that reduce T cell migration and invasion
.
Neutrophils spread
in colorectal cancer spheroids without bacteria.
But in those colorectal cancer spheroids that have bacteria, neutrophils migrate to the center of the spheroid and become trapped--- a finding that could explain why there are few T cells
in tumor areas where bacteria colonize.

Assess the spatial distribution of
bacteria within tumor tissue.
Image from Nature, 2022, doi:10.
1038/s41586-022-05435-0.

(3) When bacteria are present, tumor cells in colorectal cancer spheroids move differently
.
Tumor epithelial cells do not move as a colony, but migrate as individual cells and carry
bacteria.
This is consistent
with Bullman's previous research finding that --- Fusobacterium nucleatum often hitchhikes --- colorectal cancer metastasis.

(4) Tumor cells infected with bacteria upregulate genes
related to cancer progression and metastasis.
In oral tumor samples, these authors observed that the bacteria preferentially infected cancer epithelial cells and specific immune cells
within the patient's tumor.
Bacterial infected tumor cells have increased signal of DNA damage, a feature of
cancer.
The findings, they say, support the direct role
of bacteria in shaping these miniature niche areas.

(5) Some anticancer drugs may be effective because they are also antibacterial agents
that target bacteria that support tumor development.
The cancer-promoting bacterium Fusobacterium nucleatum is highly sensitive to a common chemotherapy drug called 5-fluorouracil (5-FU), but these authors found that E.
coli protects colon cancer cells from 5-FU
.
E.
coli apparently has a way to metabolize the drug and minimize its contact with cancer cells or other bacteria
.
"These findings point to the fact that tumor microbes are not innocent bystanders during disease progression and suggest that this tumor microbiota
should be considered when considering the best cancer treatment," Johnston said.
”

Related to the two new studies, the authors are looking at a possible link
between oral health and cancer risk.
"There is now a trend that microbes traditionally associated with inflammatory diseases of the oral cavity have been found to be linked to gastrointestinal cancers outside the oral cavity--- highlighting the fact that the oral cavity is a breeding ground
for pathogenic tumor microbes," Johnston said.
”

In addition to allowing pathogens to spread to new areas of the body, inflammation in the mouth, in the form of periodontal disease or endodontics, may be selecting and encouraging the growth
of bacteria that are better at growing in adverse conditions and able to evade the epidemic, he said.

The authors will continue to explore the possibility of manipulating the tumor microbiome to make tumors more responsive to immunotherapy or chemotherapy, and they are seeking to design microbiome-modulating therapies to prevent and treat cancer and stop it from spreading
.
They showed that tumor microbes accumulate in hard-to-reach areas of the tumor, and they have identified some of the hurdles
that must be overcome to develop these new approaches.

Bullman said, "This integrative approach to assessing the tumor microenvironment, a multi-species ecosystem, will advance our understanding of cancer biology and, I believe, will reveal new therapeutic weaknesses
for cancer.
" (Biovalley Bioon.
com)

Resources:

Jorge Luis Galeano Niño et al.
 Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer, Nature, 2022, doi:10.
1038/s41586-022-05435-0.

Kaitlyn D.
LaCourse et al.
The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota, Cell Reports, 2022, doi:10.
1016/ j.
celrep.
2022.
111625.