Different Patterns of Vascularization in Preinvasive States and at the Initial Stages of Invasive Growth of the Neoplasms

Tissue samples obtained during surgery from 90 patients with malignant neoplasms of various localizations were studied (the presence of precancerous dysplastic alterations and their transition to invasive cancer in the slides were obligatory condition). In addition to traditional histological methods, immunohistochemical reactions for detection of HIF-1α, GLUT1, CAIX, and CD31 were performed. At the precancerous stage including cancer in situ, progressive signs of reduced blood vessel density and hypoxia were observed. At the earliest stages of invasion, hypoxia was compensated by abundant vascularization of the stroma, which was confirmed by disappearance of hypoxia markers in tumor cells and their persistence in the deep layers of the tumor far from blood vessels. At the same time, the ischemic phenotype was preserved in tumor cells even in abundantly vascularized stroma, which can attest to deep metabolic changes in some tumor cells similar to the Warburg effect. Thus, the initial stages of carcinogenesis are associated with reduction of the vascular network up to the complete absence of blood vessels in the cancer in situ. After migration to the vascularized subepithelial stroma, e.g., having started invasion that compensated for hypoxia, the tumor cells no longer expressed markers of hypoxia, except the cells located far from blood vessels. In parallel, neoplastic cell clones that presumably have changed their phenotype and transformed their metabolism similar to the Warburg effect were detected. In the deep layers of the tumors, these cells coexist in different proportions. Analysis of the content of these cells, their alternation, and mutual transformation will be very valuable for estimating the sensitivity of tumor cells to therapeutic measures.