First steps of tumor-related angiogenesis

S. Paku, N. Paweletz

Research output: Contribution to journalArticle

209 Citations (Scopus)

Abstract

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 intercellular 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. Within the cisternae of the endoplasmic reticulum of EC and pericytes of the mother vessels but also of the young capillaries material with a positive reaction for laminin and collagen IV but not for fibronectin can be demonstrated. On the third day after inoculation, some nearly mature capillaries are observed. These capillaries are covered by a well-defined BL, positive for all three components and surrounded by some pericytes, but most of them do not exhibit a dilated lumen. The immunocytochemical studies of the components of the BL indicate that at the beginning of the angiogenic process the structure of the BL of the mother vessels becomes strongly altered so that in accordance with its low electron density the BL is only detectable by immunocytochemical means. We assume that this state of the BL is preferred and initiates the migration and the division of the EC. During growth of the new capillaries, the BL that is constantly synthesized by the polarized EC and that exhibits the same low electron density as the altered BL around the mother vessel guarantees a support for further migration and division of EC. The cessation of migration and division of EC and pericytes could be the consequence of the development of an electron-dense BL around the mother vessel and the newly formed capillary.

Original languageEnglish
Pages (from-to)334-346
Number of pages13
JournalLaboratory Investigation
Volume65
Issue number3
Publication statusPublished - 1991

Fingerprint

Basement Membrane
Endothelial Cells
Neoplasms
Pericytes
Connective Tissue
Immunoelectron Microscopy
Laminin
Cell Surface Extensions
Fibronectins
Electrons
Intercellular Junctions
Collagen
Cell Wall
Cell Movement
Tumor Cell Line
Endoplasmic Reticulum
Electron Microscopy
Adenocarcinoma

Keywords

  • Capillary
  • Collagen
  • Fibronectin
  • Immunocytochemistry
  • Laminin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

First steps of tumor-related angiogenesis. / Paku, S.; Paweletz, N.

In: Laboratory Investigation, Vol. 65, No. 3, 1991, p. 334-346.

Research output: Contribution to journalArticle

Paku, S & Paweletz, N 1991, 'First steps of tumor-related angiogenesis', Laboratory Investigation, vol. 65, no. 3, pp. 334-346.
Paku, S. ; Paweletz, N. / First steps of tumor-related angiogenesis. In: Laboratory Investigation. 1991 ; Vol. 65, No. 3. pp. 334-346.
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N2 - 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 intercellular 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. Within the cisternae of the endoplasmic reticulum of EC and pericytes of the mother vessels but also of the young capillaries material with a positive reaction for laminin and collagen IV but not for fibronectin can be demonstrated. On the third day after inoculation, some nearly mature capillaries are observed. These capillaries are covered by a well-defined BL, positive for all three components and surrounded by some pericytes, but most of them do not exhibit a dilated lumen. The immunocytochemical studies of the components of the BL indicate that at the beginning of the angiogenic process the structure of the BL of the mother vessels becomes strongly altered so that in accordance with its low electron density the BL is only detectable by immunocytochemical means. We assume that this state of the BL is preferred and initiates the migration and the division of the EC. During growth of the new capillaries, the BL that is constantly synthesized by the polarized EC and that exhibits the same low electron density as the altered BL around the mother vessel guarantees a support for further migration and division of EC. The cessation of migration and division of EC and pericytes could be the consequence of the development of an electron-dense BL around the mother vessel and the newly formed capillary.

AB - 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 intercellular 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. Within the cisternae of the endoplasmic reticulum of EC and pericytes of the mother vessels but also of the young capillaries material with a positive reaction for laminin and collagen IV but not for fibronectin can be demonstrated. On the third day after inoculation, some nearly mature capillaries are observed. These capillaries are covered by a well-defined BL, positive for all three components and surrounded by some pericytes, but most of them do not exhibit a dilated lumen. The immunocytochemical studies of the components of the BL indicate that at the beginning of the angiogenic process the structure of the BL of the mother vessels becomes strongly altered so that in accordance with its low electron density the BL is only detectable by immunocytochemical means. We assume that this state of the BL is preferred and initiates the migration and the division of the EC. During growth of the new capillaries, the BL that is constantly synthesized by the polarized EC and that exhibits the same low electron density as the altered BL around the mother vessel guarantees a support for further migration and division of EC. The cessation of migration and division of EC and pericytes could be the consequence of the development of an electron-dense BL around the mother vessel and the newly formed capillary.

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