Most
cancer patients die of metastatic disease, not primary
tumors, while
biological mechanisms leading to
metastases remain unclear and effective
therapies are missing. Using a mouse dorsal skin chamber model we had observed that
tumor growth and vasculature formation could be influenced by the way in vitro cultured (avascular) spheroids of N202
breast tumor cells were implanted; co-implantation of lactating breast tissue created stimulating microenvironment, whereas the absence of the graft resulted in temporary
tumor dormancy. This report addressed the issue of cellular mechanisms of the vasculogenic switch that ended the dormancy. In situ ultrastructural analysis revealed that the
tumors survived in ectopic microenvironment until some of host and tumor stem cells evolved independently into cells initiating the vasculogenic switch. The
tumor cells that survived and proliferated under hypoxic conditions for three weeks were supported by erythrogenic autophagy of others. However, the host microenvironment first responded as it would to non-immunogenic
foreign bodies, i.e., by encapsulating the
tumor spheroids with
collagen-producing fibroblasts. That led to a form of vaso-mimicry consisting of
tumor cells amid
tumor-derived
erythrosomes (synonym of erythrocytes), megakaryocytes and platelets, and encapsulating them all, the host fibroblasts. Such capsular vaso-mimicry could potentially facilitate
metastasis by fusing with morphologically similar lymphatic vessels or veins. Once incorporated into the host circulatory system,
tumor cells could be carried away passively by blood flow, regardless of their genetic heterogeneity. The fake vascular segment would have permeability properties different from genuine vascular endothelium. The capsular vaso-mimicry was different from vasculogenic mimicry earlier observed in
metastases-associated malignant
tumors where channels formed by
tumor cells were said to contain circulating blood. Structures similar to the vasculogenic mimicry were seen here as well but contained non-circulating
erythrosomes formed between
tumor nodules. The host's response to the implantation included coordinated formation of new vessels and peripheral nerves.