First steps of tumor-related angiogenesis.

We present morphological data of the early steps of tumor-induced angiogenesis and show the distribution of the three main components of the basal lamina (BL), laminin, collagen IV, and fibronectin during these early processes. Tumor cells of a line of BSp73 AS a nonmetastasizing tumor isolated from a pancreatic adenocarcinoma were injected subcutaneously into the back of BDX rats. Two days after tumor inoculation, the BL of the dilated mother vessels around the whole circumference of the vessel has either disappeared, become fragmented, or developed several successive layers. By immunoelectron microscopy, we demonstrate that the fragmented and multilayered BL is strongly stained for laminin and collagen IV but less strongly for fibronectin. Around the surface of the dilated mother vessels which are free of any detectable BL material (by electron microscopy standards), we can see accumulation of all three components in the connective tissue. Simultaneously with the alteration of the BL, the proliferation of the endothelial cells (EC) and the pericytes and the migration of the EC from the wall of the mother vessel have started. EC migration begins in two different ways. Either one EC migrates from the wall of the mother vessel into the surrounding connective tissue, or two or more EC form nearly parallel processes toward the connective tissue. The tips of these processes are connected by intracellular junctions. Around the cellular protrusions of these cells material of the BL deposited into the nearby connective tissue can be observed neither by conventional nor by immunoelectron microscopy. During the outgrowth and migration, the EC remain in contact via junctions with the EC of the original vessel. When migration during which the EC retain their polarization continues, a slit-like lumen forms immediately between the migrating EC. This lumen always remains in direct connection with the lumen of the mother vessel. It is sealed at its border by intercellular junctions. Such junctional complexes can develop a length (in sections) of several hundred micrometers. A BL detectable in the electron microscope can neither be found around the tip of the migrating EC nor around young capillaries not yet surrounded by pericytes. By immunoelectron microscopy, however, only the cellular protrusions at the tip of migrating EC are free of deposited material of the BL. The basal surface of longer (new) capillaries is covered by a continuous layer of amorphous material.(ABSTRACT TRUNCATED AT 400 WORDS)