Abstract
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.
Highlights
Two main problems persisting in oncology are related; they are (1) the incomplete understanding of the mechanism by which tumors spread from primary locations to multiple organs and (2) the lack of selective anti-cancer treatments
Attempts made to elucidate the cellular mechanism of metastasisinitiating events included retrospective extrapolation from the distribution of established metastases, namely the preference of specific tumors to metastasize in certain organs but not in others
The vasculogenic switch did occur in the absence of the homologous tissue stem cells (TSCs) from the graft but only after a considerable delay
Summary
Two main problems persisting in oncology are related; they are (1) the incomplete understanding of the mechanism by which tumors spread from primary locations to multiple organs and (2) the lack of selective anti-cancer treatments. Metastases of aggressive cancers of different types (ovarian[10,11], prostate[12,13], glioblastoma[14], as well as melanoma15) were associated with patterned vasculogenic mimicry, i.e., a network of periodic acid Schiff stained (glycoproteins containing16) “loops” that represented blood-containing micro-vascular “channels”, generated by the aggressive tumor cells without participation of endothelial cells (ECs) and independently of angiogenesis[17,18]. How these structures facilitated metastasis was not clear[19,20]
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