Abstract
Inadequate understanding of cancer biology is a problem. This work focused on cellular mechanisms of tumor vascularization. According to earlier studies, the tumor vasculature derives from host endothelial cells (angiogenesis) or their precursors of bone marrow origin circulating in the blood (neo-vasculogenesis) unlike in embryos. In this study, we observed the neo-vasculature form in multiple ways from local precursor cells. Recapitulation of primitive as well as advanced embryonal stages of vasculature formation followed co-implantation of avascular ( in vitro cultured) N202 breast tumor spheroids and homologous tissue grafts into mouse dorsal skin chambers. Ultrastructural and immunocytochemical analysis of tissue sections exposed the interactions between the tumor and the graft tissue stem cells. It revealed details of vasculature morphogenesis not seen before in either tumors or embryos. A gradual increase in complexity of the vascular morphogenesis at the tumor site reflected a range of steps in ontogenic evolution of the differentiating cells. Malignant- and surgical injury repair-related tissue growth prompted local cells to initiate extramedullar erythropoiesis and vascular patterning. The new findings included: interdependence between the extramedullar hematopoiesis and assembly of new vessels (both from the locally differentiating precursors); nucleo-cytoplasmic conversion (karyolysis) as the mechanism of erythroblast enucleation; the role of megakaryocytes and platelets in vascular pattern formation before emergence of endothelial cells; lineage relationships between hematopoietic and endothelial cells; the role of extracellular calmyrin in tissue morphogenesis; and calmyrite, a new ultrastructural entity associated with anaerobic energy metabolism. The central role of the extramedullar erythropoiesis in the formation of new vasculature (blood and vessels) emerged here as part of the tissue building process including the lymphatic system and nerves, and suggests a cellular mechanism for instigating variable properties of endothelial surfaces in different organs. Those findings are consistent with the organoblasts concept, previously discussed in a study on childhood tumors, and have implications for tissue definition.
Highlights
Some of the unsolved problems in vascular biology Tumor vascular biology research has been beleaguered with multiple controversial experimental data and unanswered questions despite the technological progress and new concepts in network biology
Cancer stem cells Judging by the activities of cells evolving in our new experimentally created environment, we retrospectively assumed the presence of their precursors, in agreement with the functional tissue stem cells (TSCs) definition
The question was which cells participated in the formation of the tumor vasculature and how did the vasculature form?At the outset, the components of the tumor niche did not have an ongoing vasculature formation
Summary
Some of the unsolved problems in vascular biology Tumor vascular biology research has been beleaguered with multiple controversial experimental data and unanswered questions despite the technological progress and new concepts in network biology. Much of the information on mapping of mammalian interactome networks waits to be experimentally validated, advancements have been made in small model organisms (yeast, Saccharomyces cerevisiae; fruit fly, Drosphila melanogaster; and worm, Caenorhabditis elegans)[1]. Richness and redundancy enabling the natural selection of evolving biological systems make their analysis difficult and call for new methods and ways of thinking[2,3]. The question of biological significance of the cellular heterogeneity within tumors remains unanswered
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