January 21, 2014

Bone Cancer Growth Reduced by Exercise

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The human skeleton is more than a structure for the organs of the body. Bones provide support, movement, protection, and produce of blood cells, store of ions and regulate the endocrine system. Without these functions, our bodies are marked for vulnerability in the face of disease and, more relevantly, cancer.

Today, chemical therapies are used worldwide as the primary choice of weapon against bone cancer. Cornell researchers have launched an initiative to study the impact of the physical environment on cancer cell growth. In 2011, Prof. Claudia Fischbach-Teschl, biomedical engineering, began a project to investigate the mechanisms through which bone loss in cancer can be reduced. Focusing on the effect of mechanical forces on bone growth, Fischbach-Teschl’s lab was able to link exercise and bone activity to slowed bone cancer growth.

Breast cancer most frequently metastasizes to the skeleton where cancer cells can take over the bone remodeling process. Secreting chemicals that direct bone behavior to stop maintaining bone mass, cancer cells are able to degrade bone which then releases growth factors supporting further tumor growth. This eventually leads to osteolysis, where bone is broken down and continually releases minerals and calcium from bone fluid to the blood.

By utilizing the released minerals, cancer cells are able to multiply more rapidly.

The study of mechanical forces on cancerous bone loss first began with research on osteoporatic bone loss. A “mouse model” was developed by Prof. Marjolein van der Meulen, mechanical engineering, to look at how mechanical forces increase the growth of cancellous, or porous, bone at risk for fracture. While the mice are asleep, an apparatus delivers controlled forces to the skeleton while varying in force strength, frequency and loading form to recreate skeleton deformation mimicking normal physiological activity. The resultant bone mass is measured to determine what kind of deformation is favorable for increased bone mass.

Because breast cancer metastasizes to cancellous bone, Maureen Lynch grad used this osteoporatic bone loss model and applied it to cancerous bone loss. “If mechanical forces can help reduce osteoporatic bone loss, maybe it can help reduce bone loss associated with cancer metastasis,” Lynch said. Bone cancer metastasis is problematic, however, because no mouse model is able to truly regenerate human metastasis in which the primary tumor begins in the breast and spreads.

“Although the mouse model is realistic in its consideration of organisms’ physiological processes such as brain signaling, nerves and digestive processes, it simply cannot tease out the direct effects we’re interested in,” Lynch said.

The main question was whether tumor cells are affected by loading or simply a by-product of the bone being active.

To find the answer, the researchers used an in-vitro system to parallel the mouse model in which cancer cells were injected into cancellous bone. A panel of pre-selected genes related to metastasis was then observed after a series of applied mechanical loading over the course of six weeks.

The results found that bone degradation nearly stopped when mechanical loading was applied to the tumor cells. In contrast, bones without mechanical loading experienced severe degradation. Evaluation of the gene panel found that a gene called runx2 was expressed less in the bone cells undergoing loading. In skeletal tumor cells, the runx2 gene was found to stimulate a chain of events resulting in bone loss.

Although mechanical loading does not directly kill tumor cells or change their ability to survive, Fischbach-Teschl’s lab was able to conclude that mechanical loading reduces the effects of osteolysis and can reduce bone cancer metastasis. Having reached this conclusion, the researchers are now looking at the correlation between the runx2 gene and the effect on bone cells.

Uncovering the molecular pathway that mediates the effects of mechanical loading shows that chemical therapies must eventually consider the physical parameters involved in chronic cancer cell growth in order to better mitigate tumor growth and metastasis. The lab continues to investigate the mediated effects of mechanical loading in conjunction with chemical cancer treatments.