There are countless microbes in our bodies, and so do
our tumors.
Over the past 5 years, researchers have found that cancerous tissue contains entire communities of bacteria and fungi
.
It now appears that some bacteria may be accomplices
in cancer.
A team led by Susan Bullman of Fred Hutchinson Cancer Center reported in Nature this week that in oral and colorectal tumors, bacteria also live inside cancer cells and produce proteins
that suppress immune responses.
Microbial invaders can set off a chain reaction that prevents the immune system from killing cancer cells, or it may help cancer metastasize to other parts of
the body.
Identifying microbes that can cause tumors to grow or spread would provide new avenues for cancer treatment, such as killing bacteria
with antibiotics.
Since each type of cancer appears to have a unique microbiome, researchers are exploring whether the microbe could be used as a diagnostic tool to detect cancer
early in blood samples.
Ravid Straussman, a cancer researcher at the Weizmann Institute of Science, said that until recently, most cancer researchers thought tumors
were sterile.
But about 10 years ago, as a postdoc at the Broad Institute, Ravid Straussman accidentally discovered that human pancreatic and colorectal cancer cells grown in the lab no longer responded to the cancer drug gemcitabine in the presence of mycoplasma contamination.
He discovered that mycoplasma "protects" cancer cells by producing enzymes that break down gemcitabine
Straussman found that injecting colon cancer mice with other types of bacteria, including strains of E.
coli, was able to render gemcitabine ineffective, while treatment with antibiotics restored gemcitabine's effectiveness
.
When he studied 113 human pancreatic cancer samples, he found that 76 percent of pancreatic cancer samples contained bacteria that produce enzymes that break down drugs, raising the question of whether they contribute
to drug resistance in human cancers.
Straussman and his colleagues are planning a clinical trial to test whether antibiotics can improve treatment
of pancreatic cancer.
Soon after, Gregory Sepich Poore, a doctoral student in Rob Knight's lab of microbiome at UC San Diego, was looking for ways to diagnose pancreatic cancer early, and inspired by Straussman's 2017 paper, Sepich Poore began searching for fragments of microbial genetic material in the Cancer Genome Atlas, a large DNA database of human
。 Gregory Sepich Poore's grandmother died of cancer, which was diagnosed too late and treatment was ineffective
.
In March 2020, Sepich Poore, Knight and their colleagues reported that each of the 33 cancers they studied contained microbial RNA and DNA, each with a unique microbiome
.
The team also found these distinct microbial signatures
in blood samples from cancer patients.
Based on their findings, Sepich Poore and Knight co-founded San Diego-based "Micronoma," a startup that aims to identify early-stage cancers in blood samples, known as liquid biopsies
.
Later in 2020, Straussman and his colleagues confirmed this: Many tumors have unique microbiomes that reside primarily within cancer cells and immune cells, not between
them.
Laurence Zitvogel, a tumor immunologist at the Gustave-Roussy Institute, said the study doesn't fully prove the role of bacteria in cancer, but it's illuminating
.
"This suggests that bacteria in tumors of the large intestine and mouth can actively disturb the immune balance
," she said.
”
Fungi also often occupy a place
in tumors.
The UCSF and Weizmann team found fungi in each of 17,000 tumor samples from 35 cancers, published in the September issue of Cell, and each cancer type is associated with a different combination of species, which helps refine the diagnostic tools
of micro-micronoma.
(Straussman is now a member of the company's scientific advisory board
.
) ）
The paper also reports another striking finding: Certain combinations of fungal species are associated with low survival rates for several cancers, with ovarian and breast cancer being the most pronounced
.
Last October, another team of researchers reported a similar situation in Cancer Cell: The presence of a specific bacterial marker appeared to be associated with
accelerated death from pancreatic cancer.
Patients without this feature had a doubling
of their 2-year survival rate after treatment.
"This is a surprising finding," said co-author Martin Blaser, a cancer microbiome researcher at the University of Rutgers and a member of
Micronoma's scientific advisory board.
But none of these findings show how fungi or bacteria can lead to worse outcomes
.
Now, Bullman and her colleagues have solved this problem
by studying tumors from 8 oral cancer patients and 19 colorectal cancer patients.
Mapping the microorganisms shows that they colonize
only specific areas of the tumor.
These infected regions contain high levels of proteins
that can inhibit cancer-fighting T cells or promote cancer growth.
The researchers found that T cells clustered outside these regions but were rarely found
inside.
(Instead, these regions contain neutrophils—immune cells
that fight infection.
) "It's conceivable that the bacteria somehow caused the T cells to leave the tumor," Blaser said
.
Using single-cell sequencing techniques, the researchers found that the bacteria preferentially infected cancerous epithelial cells located on the inner surface of the organ, and only Fusobacterium Fusobacterium and Treponema were present in them of carcinoepithelial cells show immunosuppressive and cancer-promoting effects
.
"This paper fills a critical gap" suggesting that bacteria within cancer cells may change the behavior of cells, said George Miller, a cancer physician and researcher
at Trinity Health Center in New England.
Bullman and her colleagues co-cultured Fusobacterium with colon cancer cell spheroids, a small model of human cancer, with neutrophils in the stroma, and compared
them to sterile cancer cell spheroids.
With the presence of bacteria, neutrophils tend to move towards cancer cells, similar to
what happens in patient tumor samples.
The researchers saw infected cancer cells detach from the spheroids and migrate, which Bullman thinks could be a sign that
they're metastasizing.
Zitvogel said the paper paints a picture
of how microbes are hindering the body's fight against cancer.
However, she cautions that the spheroid model "is a reductionist approach"; The human body has a diverse pool of immune cells and a diverse pool of beneficial microorganisms, and may have other mechanisms
to prevent cancer from metastasizing.
Straussman added that the study was small, including only two types of cancer, and there was still a lot of work to be done
.
But, "Bullman's research has shown us how we should explore the tumor microbiome," he said
.
"This paper is a big step
forward for the field.
"
