The biology of tumor growth has long been a mystery. It is known that tumors recruit cells to form new blood vessels -- a process called angiogenesis -- and that growth factors are necessary to promote this. But the origin of the cells that form the early, new blood vessels has been poorly understood.
Now, researchers at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center have discovered that tumor angiogenesis is dependent upon the recruitment and incorporation of bone marrow-derived precursor cells into newly formed tumor vessels. Vascular endothelial growth factor (VEGF) produced by the tumor cells induces precursor cells from the bone marrow into the tumor vessels.
These findings, published in the November issue of Nature Medicine, suggest new targets for cancer therapies and a possible blood test for cancer. Indeed, they also argue for a new paradigm in cancer biology and a significant reconceptualization of tumor growth: Prevent bone marrow stem cells from moving to the tumor and you block tumor growth.
"This is the first definitive proof that bone marrow contributes to the formation of functional blood vessels of certain tumors," said Dr. Shahin Rafii, a vascular hematologist-oncologist at Weill Cornell and one of the study's lead authors. "It increases our understanding of the mechanism by which anti-angiogenic agents block tumor growth, generating new targets for cancer therapy."
Said Dr. David Lyden, a Memorial Sloan-Kettering pediatric oncologist and another lead author: "We hope to be able to apply our findings to cancer patients, for diagnostic purposes and for treatment, and are beginning studies to determine the diagnostic potential. There are monoclonal antibodies already developed that can recognize and block mobilized blood cells, preventing tumor growth and metastasis. These are also being studied as possible treatment options."
To identify the origin of cells that contribute to tumor angiogenesis, the researchers wanted to determine if there was a role for bone marrow-derived cells in initiating and maintaining a functioning tumor blood vessel system. Rafii previously had shown that bone marrow-derived circulating endothelial precursor (CEP) cells are mobilized from the bone marrow to contribute to angiogenesis in wound healing.
In addition, findings from an earlier Memorial Sloan-Kettering study by Lyden and co-author Dr. Robert Benezra demonstrated that two proteins, Id1 and Id3, are necessary to support and sustain tumor angiogenesis. But whether these cells or proteins were also essential for tumor blood vessel formation was not known.
In the study, bone marrow cells from donor wild-type mice (normal mice) were transplanted into Id-deficient mice. The cells were marked with a protein (B-galactosidase+) that turns them blue when stained with a specific dye. Four weeks later, these mice were injected with either lymphoma cells or Lewis lung carcinoma cells (lung cancer cell lines). The Id-deficient mice developed widespread metastasis and died within 26 days, paralleling the tumor growth observed in wild-type animals. Importantly, the blue bone marrow-derived cells were seen in the vast majority of the vessels formed in the tumors.
When the reverse experiment was done -- putting Id-deficient marrow back into wild-type mice -- there was a dramatic delay in the growth of tumors. This clearly showed that the bone marrow-derived cells could promote the formation of new blood vessels by tumors and probably also are required for blood vessel formation.
"This study provides further indication of the importance of the Id genes in cancer development. They are detected in both cancer cells and in mobilized circulating endothelial cells," said Benezra, head of a laboratory in the Cell Biology Program at Memorial Sloan-Kettering and one of the study's senior authors. "Presence of these circulating cells is a potential marker for early cancer detection. We hope that this assay could be useful for diagnosing minimal residual disease."
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