Analysis: many common cancers spread initially to the bone marrow and research is underway to tackle the protection the tissue provides to these cells
Cancer therapy should target cancer cells, but is this the most effective approach? New research indicates the need for a much bigger net to tackle not just cancer cells, but the tissue in which they grow.
Until recently, cancer research focused on how to eliminate cancer cells and did not consider the surrounding tissue in which the cancer cells grow, known as the cancer’s microenvironment (or niche). As cancer is caused by damaged DNA creating faulty genes, called oncogenes, it was broadly accepted that inhibiting these oncogenes would kill the cancer cells without causing much collateral damage. Consequently, a tumour has been treated as a separate entity existing and growing in the body, almost with a life of its own.
However, there are many indications that this is not the case. For example, we know that when cancers spread, they favour certain tissues to set up home in. The "seed and soil" theory suggests the reason for this is that a cancer cell (the seed) is only able to take root if it finds the right kind of environment (soil). Although this theory was put forward more than a century ago, it is only in the last decade that research into the tumour’s microenvironment has really come to the fore.
When we hear about cancer patients whose disease has unfortunately spread, very often these "secondaries" or "metastases" have spread to the bone. If we consider some of the most common cancers (including breast, prostate, colorectal, pancreatic, kidney, bladder, thyroid etc.), their first choice of destination, if they spread, is the bone marrow. At the same time, leukemia, a cancer that develops in the bone marrow, rarely, if ever, forms metastases. Why is this and what is so habitable about the bone marrow?
To understand this, we must first consider the normal purpose of this tissue. The bone marrow is where our blood cells are produced. Red blood cells carry oxygen to tissues, while white blood cells serve as the immune system providing protection to the body against infections. They are all formed in the bone marrow from blood stem cells (hematopoietic stem and progenitor cells).
Blood stem cells can lay dormant in the bone marrow, or multiply and develop into the different blood cells, depending on the need. Interestingly, whether a blood stem cell stays inactive or multiplies is decided by the bone marrow tissue, not by the cell itself. For example, when someone comes down with a cold, a large number of white blood cells are needed to fight the infection so all the white blood cells are released from the bone marrow into the blood to find the bacteria or virus. This "emptying" of white blood cells is detected by the bone marrow microenvironment and leads to the production of activation hormones that tells dormant blood stem cells to multiply and replenish the white blood cell pool.
Cancer cells also take advantage of these survival hormones which is probably why they find the bone marrow to be the perfect location to establish a secondary tumour
Besides these activation hormones, the bone marrow produces a constant stream of survival hormones, essential to keeping the blood stem cells alive. These survival hormones are so powerful that if a blood stem cell doesn’t receive these signals, a countdown timer is activated in them that causes them to self-destruct and die within a few days. These survival hormones protect the blood stem cells from dying and also arm them against toxins and stress. Cancer cells of other tissue origin can also take advantage of these survival hormones and this is probably the reason why they often find the bone marrow microenvironment to be the perfect location to establish a secondary tumour or metastasis.
Evidence so far for this includes results from a new drug that specifically targets an oncogene (called FLT3) that acute myeloid leukemia (AML) cells have. It was noticed in the clinic that this drug has a very short-term effect. Laboratory investigation found that AML cells can be killed when this drug is added. However, when the same AML cells receive the survival signals produced by the bone marrow, they can fully resist the drug and do not die. So when a patient receives this therapy, it appears to work initially as the drug kills the AML cells that are circulating in the blood stream. However, the AML cells hiding in the bone marrow survive and, after treatment, they grow again and the full blown disease returns.
Novel therapies are now being designed specifically to tackle the protection the bone marrow provides to cancer cells. One such approach is to coax cancer cells out of the bone marrow and into the blood stream where they are more susceptible to treatments. This can be done as AML cells regularly move between the blood and the bone marrow. A new drug called Plerixafor (currently in phase II clinical trials) has been designed to bring AML cells out of the bone marrow and prevent them from returning. Once the AML cells are in the blood stream where they don’t receive the survival signals, they can be killed with chemotherapeutic drugs.
Another approach, which is underway at NUI Galway, is to make the bone marrow more hostile to cancer cells. The research group found that a specific drug changes what hormones bone marrow cells produce. By adding this drug, the bone marrow cells produce hormones that weaken, rather than protect the cancer cells, and thus making them more sensitive to chemotherapy.
In the future, drugs that make cancer cells leave the bone marrow or drugs that block the production of survival hormones can be used to sensitise cancer cells to chemotherapeutics. This will make the therapy more effective with the potential to kill all cancer cells and thus preventing the return of the cancer.
The views expressed here are those of the author and do not represent or reflect the views of RTÉ