A new study analyzing the cross-talk between bone cells and cancer cells in metastatic breast cancer models may have uncovered a weakness that can be exploited to stop breast cancer from spreading to the bone.
The study, “The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability,” was published in Cancer Cell.
When cancer metastasizes, cancer cells leave the original tumor, migrate through the bloodstream, and take up residence in other organs, often quite far from the primary tumor. Sometimes, these cells grow into metastatic lesions, which can be deadly.
In breast cancer, bone metastases, where cancerous breast cells start growing in the bone, are serious complications. Yet, the environment of the bone is very different from that of the breast. So, how does a breast cell survive in this new landscape, much less grow into a clinically relevant tumor? By better understanding this process, researchers hope to find ways to stop it.
Researchers examined the gene expression profiles (which genes were turned on or off) of different breast cancer metastases in published datasets, and they noticed that a number of genes downstream of calcium signaling were increased in bone metastases as compared to metastases at other locations.
Some cells use calcium gradients — the amount of calcium inside versus outside of the cell, or within certain compartments in a cell — to regulate a host of functions, including growth. Calcium signaling is particularly important for bone cells, so the researchers wondered whether this signaling pathway might be altered in breast cancer cells growing in the same place as bone cells.
The investigators used a mouse model and a 3D culture model of breast cancer to test their hypotheses. They first confirmed these models reflected the results from the databases, and they did: Breast cancer cells growing in mouse bones showed similar changes in calcium signaling-related genes, but cells grown in the mammary tissue did not.
In order to test whether calcium signaling was playing a role in breast cancer bone metastasis growth, the investigators inhibited calcium signaling in their models.
They used a combination of methods, including pharmacological inhibitors and cells producing abnormal proteins from the calcium signaling pathway, and they found that inhibiting calcium signaling indeed diminished growth. So, bone-metastatic breast cancer cells are dependent on calcium signaling.
Despite this dependency, breast cancer cells were not especially good at taking in calcium from their surroundings when the researchers tested this. Instead, the study found, calcium is shuttled to cancer cells by bone cells through connections in cell membranes called gap junctions.
“These gap junctions work like a tunnel through which calcium travels from the osteogenic [bone] cell to the cancer cell. The transfer of calcium can promote the early outgrowth of tumor cells that could lead to major bone metastasis,” said Xiang Zhang, PhD, an author on the study. The study found that other substances also could move through the junctions in both directions, allowing for cross-talk between bone and cancer cells.
The researchers further found that gap junction proteins are increased in bone metastatic cells. Disrupting these proteins inhibited cell growth, further supporting the critical role of these junctions in metastatic cell growth. However, disrupting gap junctions in patients would have major consequences, as these junctions are necessary for a lot of normal functions.
In order to find a more therapeutically relevant strategy to exploit their discovery, investigators turned back to the genes of calcium signaling. They found they could prevent bone metastasis in their model by disrupting the function of these genes, which are more specific to cancer cells.
“A very short treatment that combined the drug everolimus, an mTOR inhibitor, and arsenic trioxide that affects calcium transport, significantly suppressed growth of bone metastasis in our mouse model,” said Zhang. As these drugs are already FDA-approved for other purposes, it might be easier to get them to be applied in clinics — although that’s still a long way away.
“We hope that with this and other studies in the lab we can achieve a better understanding of the ‘conversation’ between cancer and bone marrow, so we can stop cancer cells before they disseminate to other places,” Zhang said.