SAN ANTONIO-Bone tissue provides a high concentration of specific growth factors embedded in the bone matrix, giving metastatic lesions there an environment unique to bone. Researchers are uncovering many of the factors that interact within that environment, some of which, only recently discovered, were described and discussed here at the International Meeting on Cancer Induced Bone Disease.
The importance of new discoveries in the area of metastases to bone is easy to understand, said Theresa Guise, MD, Professor of Medicine in the Division of Endocrinology at the University of Virginia, the co-moderator of a session on breast cancer and bone metastasis. Traditional therapy hasn't really cured bone metastasis.
Therapies targeting these new metastatic tumor factors will not replace traditional therapy as single agents, but will be used in combination with standard anticancer therapies, she predicted in an interview.
[Combination therapy] will hopefully provide a cure for bone metastases. All of us are trying to find a common kind of 'master switch' of bone microenvironment that may control these different factors. You can target many factors and not get the end result, so to understand what is regulating all of those factors is really the key to identifying what would be a good target.
Dr. Guise said researchers have not yet identified the ideal target in bone metastases but that there are some strong suspects.
RANK ligand may be one of the common regulatory targets because it's a central regulator of osteoplast formation, but it could also have a role in tumor growth as well, Dr. Guise said.
Figure. Theresa Guis...Image Tools
RANK (receptor activator of nuclear factor kappa B) ligand is produced by the osteoblast and can be bound physically to that cell as a protein, or it can circulate. And there are some matrix metalloproteinases that shed RANK ligand. It's the most potent stimulator of osteoblast differentiation, she said.
Another central regulatory mechanism might be transforming growth factor (TGF)-beta, which controls much of the tumor production of osteolytic and osteoblastic factors.
And hypoxia may also be a central regulatory mechanism because hypoxia occurs in bone metastasis, and that stimulates a host of factors that are similar to those regulated by TGF-beta, Dr. Guise added.
Beta 2-Microglobulin Another Target
Another target is the growth factor beta 2-microglobulin. Although it is not a master switch, some researchers believe its overexpression may be a mechanism by which the primary tumor mediates bone metastases, Dr. Guise said.
[Beta 2-microglobulin] is a very interesting and novel target. It is breakthroughs like these that are very exciting and may provide new insights to the treatment.
The scientist credited with being the first to identify beta 2-microglobulin as a possible mechanism for mediating bone metastases is Leland W. K. Chung, PhD, Professor and Director of the Molecular Urology and Therapeutics Program in the Department of Urology at Emory University School of Medicine.
Dr. Chung, cochair of a session on prostate cancer and bone metastasis, presented his latest data on beta 2-microglobulin, a soluble protein overexpressed in some cancers and secreted by host inflammatory cells.
We believe beta 2-microglobulin is a major growth factor whose abnormal function and signaling could lead to prostate cancer metastases and their survival in the bone, Dr. Chung said in an interview after his presentation.
He said that he and Mary C. Farach-Carson, PhD, Director of the Center for Translational Cancer Research at the University of Delaware, had been searching for soluble factors such as beta 2-microglobulin that might play a dominant role in influencing the balance between the cancer cell and the host stromal cell in the microenvironment.
When mice transfected with cell lines from breast cancer, lung cancer, and renal cell carcinoma were treated with inhibitors of beta 2-microglobulin, the tumors cleared, Dr. Chung reported.
As we all know, we still have not prolonged survival in prostate cancer despite years of research. Therefore we feel that if we can clean up the bone and make the bone tumor disappear, we can eliminate cytokines that cause cachexia and pain in these patients.
Figure. Leland W. K....Image Tools
He said that if an agent could inhibit factors such as beta 2-microglobulin and thereby inhibit bone metastases, it could feasibly be combined with an antiangiogenic agent, which would have less impact on bone.
Osteomimicry
Another focus of Dr. Chung's research is osteomimicry, a term he coined to describe the ability of prostate cancer cells to mimic bone gene expression and behaviors in the stromal cell.
In osteomimicry, prostate cancer cells in the primary tumor activate embryonic-like programs latent in the adult, producing a form of stem cell that acts like a bone cell and expresses highly restricted bone proteins such as osteocalcin, osteopontin, bone sialoprotein, osteonectin, and RANK-ligand. These proteins are then used in the metastatic process to support cancer cell growth and survival in the skeleton.
In a review article published in May, Dr. Chung's group wrote that in clinical specimens, this can be observed in cancer cells still residing in the primary tumor (American Journal of Pathology 2006;168:1405-1412).
Cancer cells mimic the bone probably by changing the methylational status of the promoter, which allows them to express a certain gene at a certain time, he explained. The cells are also influenced by key soluble factors that may be released by inflammatory cells, such as beta 2-microglobulin.
Through the combination of these factors and the responding cells, the cells acquire the ability of making something they normally don't make, he said. Normal prostate cells don't make bone-like protein. Prostate cancer cells also can actually form mineralized bone if put in the right conditions-that's pretty amazing.
Osteomimicry may be the reason prostate cancer cells can move to the bone, survive there, and then overcome the dormancy, he said. And when dormant, they are probably resistant to chemotherapy, he added.
And other people are showing that cancer cells have the property of mimicry in breast cancer and lung cancer as well, perhaps all solid tumors.
Dr. Chung named two postdoctoral fellows at Emory who contributed significantly to beta 2-microglobulin research in studies published at the end of last year: Wen-Chin Huang, PhD (Huang W et al: Cancer Research 2006;66:9108-9116), and Takeo Nomura, PhD (Nomura T et al: Clinical Cancer Research 2006;12:7294-7305).
Dr. Guise, asked for her thoughts on osteomimicry, said, We really know very little about the role of the stem cell in bone metastasis, but we're beginning to learn. It's something that's evolving, and it should be a very interesting mechanism to target with therapy if that pans out.
© 2007 Lippincott Williams & Wilkins, Inc.