Bone healing stem cells provide a "free ride" for cancer cells?

New research may help explain why long-dormant cancer cells suddenly become more aggressive
.
Soon after the primary tumor forms, cancer cells enter the bloodstream and invade bones and other tissues
.
In bones, these diffuse tumor cells (DTCs) hide in a niche around blood vessels, where they can remain dormant for a long time before unexplained awakening, ready to colonize
surrounding tissues.
Colonization — the final step in bone metastasis — typically occurs years after removal of the primary tumor, and its effects are estimated to kill hundreds of thousands of people in the United States each year
.

"If the cancer is already in the bone, what triggers it to grow back?" Cancer researchers at Baylor College of Medicine are trying to answer that question
.

Case studies have shown that bone metastases occur after dental implant surgery, and epidemiological studies have shown an increased risk of bone metastases after experiencing fractures, leading researchers to assume that the bone remodeling process after injury may initiate cancer cell division
.
In a study published October 26 in Cancer Discovery, Xiang H.
-F.
Zhang and his colleagues found that after fractures, DTCs in mice bind to perivascular stem cells, which the body sends to the site of injury to begin the healing process
.
Once they reach the fracture site, the cancer cells appear to proliferate along with bone remodeling, in which damaged bone is absorbed and new bone forms
in its place.

"This is a very important study because it validates clinical data that suggests that increased bone resorption promotes the growth of tumors in the bone, and it provides a mechanism by which this happens," said Theresa A.
, a cancer researcher at the University of Texas MD Anderson Cancer Center who studies the mechanisms of bone metastasis.
Guise wrote in an email that she was not involved in the effort
.
"These results advance our understanding of bone metastases and point to possible reasons why
patients with bone metastases perform poorly when fractured.
"

Xiang H.
-F.
Zhang's early research showed that bone metastases tend to occur in osteogenic niches, the areas where
osteoblasts and their cellular precursors live.
The discovery prompted him and his colleagues to delve deeper into why bone remodeling exacerbates the spread
of cancer cells.
To confirm this effect, they focused on when bone remodeling was most active: after a
fracture.
The team implanted murine-derived tumors with bioluminescent genes into
mice.
After about 17 days, the researchers removed the tumor and broke the femurs
of some of the animals.
About 17 days after allowing bone remodeling to occur, biofluorescence imaging showed that the cancer cells had spread widely in the fractured femur and almost no cancer cells in
the uninjured bone.

The researchers then explored mechanisms that could explain this result
by repeating the bioluminescence imaging experiment in mice with depleted bone cell types.
Mice with reduced levels of NG2+ cells (a type of stem cell that can differentiate into osteoblasts) showed fewer bone metastases from fractures than mice with normal levels of NG2+ cells, suggesting that NG2+ cells played a role
in transporting cancer cells to the fracture site.
NG2+ cells, which reside in the space around blood vessels like DTCs, appear to migrate to osteogenic niches, Zhang said, and his experiments show that "the normal function of these cells is to promote bone remodeling
.
" "Spatial analysis of bone metastatic tissue revealed that NG2+ cells and DTCs were adjacent and often overlapping, providing further evidence for a link between the two cell types that could explain the link between
bone remodeling and tumor growth.
"

Zhang said it would be nearly impossible to capture the real-time migration of the two types of cells in animals with current techniques, but in vitro experiments have shown that NG2+ and cancer cells have the ability to adhere to each other and move
together.
"So, the two cell types can definitely work together," he said, adding that two forms of an adhesion molecule called cadherin are the glue
between them.

The form of adhesion molecules expressed by stem cells is called N-cadherin, while the type of adhesion molecule produced by cancer cells is called E-cadherin
.

To find out whether the process they observed in mice might also apply to humans, Zhang and colleagues analyzed protein expression in samples of surgically removed early-stage human bone metastases caused by different types of cancer, including breast, prostate, colon and lung cancers
.
The researchers found NG2+ and N-cadherin in cells near cancer cells, suggesting that bone remodeling may affect metastasis regardless of the original cancer cell type, though Zhang said the researchers haven't looked at
this in detail.

"The technology used here is state-of-the-art and the data is comprehensive," Guise said, "and the icing on the cake is that the authors validated their experimental findings on bone metastasis in humans, which further strengthens this research
.
" ”

In further experiments, NG2+ stem cell-depleted mice had fewer bone colonizations of DTCs even in the absence of fractures, suggesting that even the ongoing homeostasis bone remodeling may exacerbate bone metastasis
.
Zhang said that means people who experience faster bone remodeling, such as those with osteoporosis, may be at higher risk of
metastasis.
Guise agrees with this assessment, but notes that osteoporosis in older adults is not always associated
with faster bone resorption.

Zhang said it is possible to prevent bone metastasis
by attacking the binding between N-cadherin and E-cadherin molecules expressed by cancer cells.
However, the researchers found that eliminating N-cadherin slowed the rate of bone remodeling in
mice.
Preventing bone metastasis by hindering bone healing is not a viable approach, he said, so he and his colleagues will focus on attacking E-cadherin
in future studies.

While Guise says Zhang's proposed treatment is promising, she notes that "treatment must only target bone, as the loss of E-cadherin may promote malignancy in non-bone sites
.
" She explained that mutations in the gene that normally encode E-cadherin have been linked to
breast and stomach cancer in humans.

Blocking the connections between cadherin molecules may be more than just preventing bone metastasis, Zhang said, because as tumors grow, DTCs can metastasize from bone to other organs, where they may metastasize
again.
"We do think that if we can break that link, we can reduce not only the risk of bone metastasis, but also further metastasis to other organs
.
"