Breast cancer FGF-2 and VEGF calls in mesenchymal stem cells

Augusta, Georgia -

It is believed by many that tissue resident stem cells subsequent to accumulating DNA damage lose proliferative controls and transform into tumors. For example, there is a classical study in which mice were infected with h.pylori and gastric cancer was allowed to develop. Strikingly, the gastric cancer was derived from bone marrow stem cells which had migrated to heal the damaged stomach tissue and subsequently transformed into cancer cells (Houghton et al Gastric cancer originating from bone marrow-derived cells.Science. 2004 Nov 26;306(5701):1568-71)

One interesting finding is that not only do cancer cells seem to attract various types of stem cells, but that in some situation administration of healthy stem cells can inhibit the cancer growth. Evan Synder from San Diego has actually been proposing these types of approaches for targeting brain tumors. For example, in his issued US patent 7,186,409 he teaches that neural stem cells can be used as vectors to carry toxic payloads to brain tumors.

A very important question is how do tumor cells call in stem cells? Well off the top of one's head, one would imaging that since stem cells are usually attracted by injury signals, similar to the ones that call in bone marrow stem cells to home into injured myocardium after a heart attack and since tumors are considered "wounds that never heal", it may be possible that signals such as SDF-1 may be chemoattracting stem cells to tumor cells.

In a recent study (Ritter et al. Breast Cancer Cell-Derived Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor Are Chemoattractants for Bone Marrow Stromal Stem Cells. Ann Surg. 2008 Feb;247(2):310-314) the interaction between tumors and stem cells was examined. Researchers used in vitro breast cancer cell lines to determine that these cells have a chemoattracting property to bone marrow derived mesenchymal stem cells when placed in Boyden chambers.

Chemoattractants of relevance were VEGF and FGF-2. Particularly mesenchymal stem cells expressed receptors for these cytokines, and the tumor cells made these cytokines. The cytokines were found in plasma of cancer patients at high enough concentrations to induce migration of mesenchymal stem cells. Additionally, migration could be inhibited in vitro by blockade of VEGF or FGF-2.

These data provide some clues as to the molecular interaction between tumor cells and mesenchymal stem cells. Since VEGF is clinically inhibited by the anticancer drug Avastin, one wonders whether this affects the interaction of the mesenchymal stem cell with tumor cells.

An additional point of interest is whether the FGF-2 produced by the tumor has other properties besides stimulation of mesenchymal stem cell migration. For example, it is known that FGF-2 increases endothelial health. So one question would be, "are the flow mediated vasodilation responses better in cancer patients?"