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Researchers identify new role for cytokine VEGFA in the metastasis of neuroblastoma.

Healthy bone is continuously involved in a dynamic process that includes bone deposition and bone resorption. However, when a person has cancer that spreads to the bone and bone marrow, the tissue becomes increasingly fragile, and this process is disrupted, usually leading to increased bone resorption.

Now investigators at Children’s Hospital Los Angeles and the University of Southern California reported a surprising discovery, when neuroblastoma cells metastasize to the bone, there initially occurs an increase in bone deposition, not resorption. They also determined that this process is driven by a chemical messenger called VEGFA.  The study is published in the International Journal of Cancer.

Neuroblastoma is the most common extra-cranial solid tumour occurring during childhood and frequently metastasizes to the bone and bone marrow, making the disease more difficult for doctors to treat and conferring a worse prognosis for patients. Teams of scientists have been working to determine what causes a tumour to metastasize, knowing it is an interaction between tumour cells and the metastatic site, called the microenvironment.

The team explain that metastasis results from a vicious cycle, tumour cells accelerate bone deposition, which releases physiological factors that feed tumour cells.  The microenvironment includes the connective tissue, or stromal cells in the bone marrow, the cells that form and resorb bone along with other cells and growth factors.

Stroma includes a population of pluripotent progenitor cells that are able to become bone, muscle, fat or cartilage. A growth factor called bone morphogenetic protein, or BMP, drives the progenitor cells on the path to form bone. When BMP was added to progenitor and NB cells, the investigators expected bone deposition but they found more of it than anticipated. Using microarray analysis, they determined this increase to be mediated by VEGFA. In other experiments they specifically blocked VEGFA and found an increase in bone-resorbing cells and areas of severe bone loss.

The team summise that for years the medical community have known that the microenvironment was key to understanding metastatic neuroblastoma.  Now, the current study has identified a new role for VEGFA, laying the groundwork for the development of therapeutics to target it.

Source:  Children’s Hospital Los Angeles

 

Expression of mVEGFA in bones injected with human CHLA-255 NBL cells. H&E stain of a section through a femur three weeks postinjection with CHLA-255 cells in the BM cavity (upper left). NBL cells were detected with an anti-TH antibody (upper right). Detail of a tumor nodule outlined in red (lower left). Immunohistochemistry on an adjacent section with an antimouse VEGFA antibody, positive cells from the host tissue are surrounding the tumor (lower middle). Detail showing VEGFA-positive cells in close proximity of the bone and surrounding the tumor border (lower right). B: bone; T: tumor; GP: growth plate. Scale bar = 50 μm.  Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.  Sposto et al 2015.
Expression of mVEGFA in bones injected with human CHLA-255 NBL cells. H&E stain of a section through a femur three weeks postinjection with CHLA-255 cells in the BM cavity (upper left). NBL cells were detected with an anti-TH antibody (upper right). Detail of a tumor nodule outlined in red (lower left). Immunohistochemistry on an adjacent section with an antimouse VEGFA antibody, positive cells from the host tissue are surrounding the tumor (lower middle). Detail showing VEGFA-positive cells in close proximity of the bone and surrounding the tumor border (lower right). B: bone; T: tumor; GP: growth plate. Scale bar = 50 μm. Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis. Sposto et al 2015.

 

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