Stem cells, cancer progression and metastasis (part II) – angiogenesis

by Alexey Bersenev on July 25, 2008 · 0 comments

in cancer, under discussion

In this series of posts I summarize modern knowledge about roles of stem and progenitor populations of bone marrow in cancer progression. Today is part II – angiogenesis.

The importance of angiogenesis for tumor development was proposed by Judah Folkman back in 1971 and originally extensively studied in his laboratory at Harvard Medical School.

In the last decade many of the cell populations in bone marrow (BM) were described as participants of tumor angiogenesis and stroma formation: endothelial progenitor cells (EPC), mesenchymal stromal cells (MSC) and hematopoietic cells (including stem cells and different progenitors). According to a modern concept, bone marrow cells are “the bad guys” – when the tumor is present in our body, cells mobilize into bloodstream, migrate and recruit into the tumor, where they form vasculature and stroma. That leads to tumor growth and progression.

It is a widely held belief that tumor angiogenesis and growth critically depend on recruited BM-derived endothelial progenitors cells (EPC), based on many published studies.

Mobilization and contribution bone marrow-derived cells to tumor angiogenesis

(Angiogenic factors that are released by tumour cells induce co-mobilization of VEGFR1+ haematopoietic stem cells and VEGFR2+ circulating endothelial precursors (CEPs) from the bone marrow. Recruitment of both CEPs and haematopoietic cells is required for the functional incorporation of differentiated CEPs into the tumour vasculature. Credit: Shahin Rafii, et al, 2002, modified)

However, contribution level of BM-derived EPC in tumor neovasculature and particular neo-endothelium remain unclear. Authors shows that circulating EPC (which have BM origin) could constitute from undetectable level up to 50% of tumor neovessels. Thus, the mechanisms of contribution of the BM-derived cells to tumor angiogenesis remain controversial.

Authors of the recent work, challenged modern concept of BM-derived endothelial progenitors contribution to tumor angiogenesis. The claim, pointed out in the title was that these cells do not contribute to vascular endothelium and are not needed for tumor growth. Researchers extensively studied all of the possibilities to induce angiogenesis with simultaneous mobilization of EPC from bone marrow, including tumor inoculation models. Also a few mouse models were used, including pairs of parabiotic mice, and wide range of methods were used in different time points in order to analyze the contribution of BM-derived cells to endothelium. Conclusion of all of these experiments was that “cancer growth does not required BM-derived endothelial progenitors“.
Authors noticed that earlier published studies, describing circulating EPC and their role in tumor/tissue angiogenesis, have been misinterpreted because of technical difficultes and less advanced techniques, which did not allow for a way to distinguish EPC from another BM-derived tissue-infiltrating hematopoietic cell: leukocytes, usually located very close to blood vessel wall.

It seem like a tumor is able to build its own vasculature without angiogeneic precursors from BM. This conclusion is complemented by another work, published recently in PLoS ONE, which showed that precancerous stem cells in situ (within the tumor mass) can make vasculature for tumor itself. Very interesting findings!

So, the contribution of bone marrow-derived endothelial progenitors to tumor angiogenesis seems to be insignificant. Hematopoietic stem and progenitor cells, recruited from BM, could play a role in inflammation and immune reactions within the tumor’s stroma during progression and complications. Mesenchymal stromal progenitors participate in making stroma of the tumor. All BM-derived cells in the tumor released cytokines and growth factors, supported and promoted angiogenesis, tumor growth and mobilization of more cells from the marrow. Using the ability of BM cells to migrate to tumor (so called “pathotropism“), we can design cell vehicle systems for drugs or gene delivery, including anti-angiogenic therapy.

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