New Findings: Cancer recurrence stems from cell competition

On November 7, 2022, researchers at the University of Texas Southwestern showed that a normal process known as cell competition, in which healthy tissue eliminates unhealthy cells, may be what causes
cancer to recur months or years after patients are declared cancer-free.

Dr.
Srinivas Malladi

The findings, published in the journal Cancer Discovery, could lead to better treatments and even ways
to prevent tumors from metastasizing or spreading to different parts of the body.

"Our findings suggest that cell competition within the primary tumor leads to less adapted cells entering the cycle
.
But not all of these displaced cells die," said study leader Srinivas Malladi, Ph.
D.
, assistant professor of pathology at UTSW and a member of the
Harold C.
Simmons Comprehensive Cancer Center.
Some cells with metastatic potential survive in the circulatory system, persist in distal organs, and trigger metastasis
.

Metastasis is common
in most cancers.
Clear cell kidney cancer (ccRCC) is the most common type of kidney cancer, and after the primary tumor is removed, new metastatic lesions tend to develop well, a process known as heterochronous metastasis
.
Researchers already know that metachronous metastasis can occur months or years later, when many patients and their doctors think they are cancer-free
.
But how this happened is unknown
.

To find out, Dr.
Malladi and his colleagues created a mouse model
of allochronous transfer by implanting human ccRCC cells carrying the extra gene.
These cells carry extra genes that make them glow and resist an antibiotic
called hygromycin.
Four weeks later, the researchers surgically removed the primary tumor that formed at the implant site and then continued to monitor the animals
' metastasis through bioluminescence imaging.
Although none of the mice developed metastatic tumors for the next five months, the researchers found living cells in the lungs of these mice that glow and resist hygromycin
.

When the researchers cultured these latent metastatic (Lat-M) cells and primary tumor cells in a dish, they found that the primary tumor cells took over the mixture and more Lat-M cells ended up in the medium—both signs that Lat-M cells were "lost" in competition with primary tumor cells
.
However, when the researchers implanted Lat-M cells alone into mice, they effectively grew tumors
.

"Although Lat-M cells are 'losers,' metastasizing from the primary tumor," Dr.
Malladi explains, "they are 'winners'
when they grow individually.
" "These findings suggest that disease progression is not necessarily driven by dominant, aggressive cloning, but may be driven
by indomitant, less suitable clones within the primary tumor.
"

Further research uncovered a gene called SPARC, which appears to play a key role
in Lat-M cell translocation and the establishment of distant organs.
When SPARC activity in the primary tumor decreases, a decrease in Lat-M cell translocation can be observed, and the loss of SPARC in Lat-M cells planted in the lungs leads to an increase
in metastatic burden.
Dr.
Malladi believes that other genes to be discovered may also be important
in this process.
Ultimately, he says, analyzing the genes of the primary tumor surgically removed from patients could reveal which individuals need to be more closely monitored for metastatic metastasis
after surgery.
Pharmaceutical companies may one day work on these genes to prevent Lat-M cells from leaving the primary tumor, a strategy that may prevent the abnormal metastasis
of a range of cancers.