PubMed · 15422804
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K FOCHEM. 1950-06-01. [Osteoblastic sarcoma].. https://pubmed.ncbi.nlm.nih.gov/15422804/
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Bone is the second most common site of metastasis in neuroblastoma. Over the last several years, our understanding of the mechanism of bone metastasis in neuroblastoma has significantly improved. Like breast cancer and myeloma, neuroblastoma cells activate osteoclasts to form osteolytic lesions. Activation occurs via the receptor activator of NFkappaB ligand (RANKL) or in the absence of RANKL via activation of bone marrow mesenchymal stem cells and stimulation by these cells of the expression of IL-6, a potent osteoclast activating factor. Several targets for therapeutic intervention can now be identified. Inhibition of osteoclast activation by bisphosphonates has already shown to be effective in preclinical models of neuroblastoma bone metastasis and should now be tested in phase I clinical studies. Inhibition of RANKL and IL-6 are other potential targets that require preclinical studies before being tested in patients. This article provides a review of our current understanding of the mechanisms involved in bone metastasis in neuroblastoma and discusses how this knowledge is leading to the identification of new targets for therapeutic intervention.
The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics.
Prostate adenocarcinoma metastasizes to the skeleton more frequently than any other organ. An underlying cause of this phenomenon may be the ability of bone-produced factors to specifically select disseminated prostate cancer cells that are susceptible to their trophic effects. Platelet-derived growth factor (PDGF), a potent mitogen for both normal and tumor cells, is produced in several tissues including bone, where it is synthesized by both osteoblasts and osteoclasts. Here, we show that PDGF causes a significantly stronger activation of the Akt/PKB survival pathway in bone-metastatic prostate cancer cells compared to nonmetastatic cells. Normal prostate epithelial cells and DU-145 prostate cells, originally derived from a brain metastasis, are not responsive to PDGF. In contrast, epidermal growth factor stimulates Akt to the same extent in all prostate cells tested. This difference in PDGF responsiveness depends on the higher expression of alpha-PDGFR in bone-metastatic compared to nonmetastatic prostate cells and the lack of alpha-PDGFR expression in normal and metastatic prostate cells derived from tissues other than bone. Thus, alpha-PDGFR expression might identify prostate cancer cells with the highest propensity to metastasize to the skeleton.