Tumour cell growth is impacted by mineralization of bone matrix: Study
Washington DC, US: The mineralization of the bone matrix, a fibrous mesh of organic and inorganic components that determines the distinct biochemical and biomechanical properties of our skeleton, has now been discovered by an interdisciplinary Cornell team as a new mechanism controlling tumour growth in the skeleton, the primary site of breast cancer metastasis.
In their article, "Bone-Matrix Mineralization Dampens Integrin-Mediated Mechanosignalling and Metastatic Progression in Breast Cancer," which appeared in Nature Biomedical Engineering. Siyoung Choi, a research associate, and Matthew Whitman, a doctoral student, are the co-lead authors.
The project is the result of a recent partnership between co-senior authors Lara Estroff, the Herbert Fisk Johnson Professor of Industrial Chemistry, and Claudia Fischbach, the Stanley Bryer 1946 Professor of Biomedical Engineering, both at Cornell Engineering. The two have been researching the metastatic spread of breast cancer to the bone for more than ten years.
To understand how the tissue microenvironment controls cancer in various contexts, Fischbach's lab uses biomaterials in conjunction with cellular and tissue engineering techniques, while Estroff's team focuses on biomineralization, or how living things regulate the growth of crystals in their tissues.
“We know that cancer cells behave like seeds that need the right soil to grow, and we’re very interested in how the extracellular matrix, which is basically the material in between cells that holds everything together, affects tumour growth,” Fischbach said.
During physiological mineralization, bone mineral particles are deposited in and around collagen type I fibres.
This process occurs naturally and is necessary for bone health but decreases with age – for example, due to hormonal changes as seen in women undergoing menopause. It can also result from dietary changes or chemotherapy.
A connection between reduced bone health and the behaviour of tumour cells is well-established. For example, decreased bone mineral density has been correlated with an increased risk for metastasis, and incomplete fracture healing has been shown to enhance bone metastasis.
However, no one had been able to isolate which specific role bone-matrix mineralization plays in this process.
“You can’t study some these connections unless you have model systems in which you can control bone matrix properties in a defined way,” Fischbach said.
The researchers were able to create such systems by combining organic and inorganic matrix components, including collagen and the bone mineral hydroxyapatite, in a manner that mimicked physiological and pathologic mineralization.
Estroff led the necessary materials synthesis and characterization techniques of the different bone matrix models, which the team then used to investigate tumour cell behaviour, first in vitro and then in vivo through mouse models.
The presence of bone minerals reduced the growth of tumour cells in both settings. The presence of minerals also caused tumour cells to promote genes that were associated with better patient prognosis. These findings suggest that a healthy bone matrix can reduce the risk of breast cancer skeletal metastasis.
Co-authors Matthew Paszek, associate professor in the Smith School of Chemical and Biomolecular Engineering, and Olivier Elemento, director of the Englander Institute for Precision Medicine and a professor of physiology and biophysics and of computational genomics in computational biomedicine at Weill Cornell Medicine, helped elucidate how bone matrix regulates cellular mechanosignaling, and connect the potential molecular mechanisms to patient data.
“This study basically shows for the first time that physiological interactions between mineral particles and collagen may be able to inhibit the activation of tumour cells that have spread to the bone,” Fischbach said.
“Now we’re broadly interested in how other cell types are influenced by varied bone-matrix mineralization. And how do mineral-dependent changes of their behaviour regulate tumour cells?”
