In the final episode of this series, I want to talk about metastasis of cancer cells and microcirculation in the tumor tissue. These are also interesting topics concerning the therapy and outcome of cancer. Let’s get ready for the final!
Microcirculation in Tumor Tissue
First, we need to differentiate Vasculogenesis from Angiogenesis. Vasculogenesis refers to the differentiation of precursor cells / angioblasts into endothelial cells in the course of embryogenesis.
Angiogenesis, on the other hand, encompasses the process of sprouting new vascular extensions from existing postcapillary venules.
In adults, angiogenesis takes place physiologically during wound healing processes, during the menstrual cycle in the course of the proliferation of the endometrium, in hypoxic states and, for example, during training or building of muscle tissue.
In physiological angiogenesis, pro-angiogenic factors ensure increased endothelial proliferation and the release of proteases to break down the ECM. The pericytes serve as a guide and support structure for the endothelium by stabilizing the growing vascular extension. If angiogenic factors are present, the pericyte "dropout" occurs, which explains the leading function of the pericytes.Ultimately, an orderly network of arterial vessels, capillary bed and venous vessels is created, which supplies the tissue with sufficient oxygen and nutrients.
From a volume of approx. 2 mm³, tumor tissue needs a connection to the vascular system since the supply via diffusion is insufficient. Tumor cells therefore release massive amounts of VEGF (vascular endothelial growth factor) and angiopoietin through the physiological mechanism in hypoxia, which stimulates the angiogenesis of nearby vessels.
The balance of anti and proangiogenic factors in the tumor tissue is shifted towards the proangiogenic mediators, which is known as the "angiogenic switch"
The vascular connection makes the tumor independent and metastasis is promoted!
It is characteristic of tumor angiogenesis that there is no ordered network as in physiological angiogenesis, but a chaotic vascular network - winding vessels, strong branches, short circuits. In addition, the capillaries of tumor angiogenesis are immature, very permeable and have fewer stabilizing cells surrounding them - typical jumps in the diameter of the vessels can be seen.
Overall, the supply is worse than in normal tissue, so that areas of undersupply arise that are called hypoxic nests. It is precisely these cells that mostly change their metabolism due to the hypoxia and tend to have an increased mutation rate, which means that they can easily metastasize via the very permeable tumor vessels - this is problematic with regard to the poor accessibility by chemotherapeutic agents!
Tumor angiogenesis broken down into 4 steps:
Activation of the endothelial cells by pro angiogenic factors from the tumor tissue
Degradation of the basement membrane of the capillary
Migration & proliferation of the endothelial cells
New formation of a basement membrane around the immature tumor vessel
Tumor angiogenesis is part of tumor therapy and research. Since a vascular network is already in place at the time of diagnosis, decoy receptors for VEGF are not as therapeutically successful as expected - but they are effective enough to continue to be used.
Decoy receptors are soluble, free receptors that bind the corresponding messenger substances
The latest research is aimed at increasing the endothelial communication of the tumor endothelial cells again - this is intended to reorganize and restructure the tumor vessel network in order to better reach the tumor with chemotherapeutic agents.
|Proangiogenic Mediators||Antiangiogenic Mediators|
Metastasis describes the process in which the cells of a tumor cluster detach and migrate to other tissue or generally elsewhere. The Metastasis can be structured into the following steps:
After locally invasive, destructive growth, in which the tumor destroys the adjacent tissue, cell-cell contacts (especially cadherins) begin to partially break away
The ECM is temporarily and reversibly degraded by means of metalloproteases, serine proteases and collagenases, so that after epithelial-mesenchyme transition (ETM) the tumor cell can begin an amoeboid locomotion using the actin filament system and extracellular receptors that interact with the tumor stroma.
ETM serves to improve migration properties
The migrating tumor cells penetrate the metastatic pathways (lymphatic system, blood vessels, body cavity), which is known as intravasation
The migrated tumor cells are initially carried along the anatomical course of the invaded structure - in blood vessels, tumor cells protect themselves from the tumoricidal aggravation of the blood through local coagulation processes that surround them with fibrin and platelets and thus form a "protective armor" (tumor cell embolus)
The tumor cell embolus with activated coagulation also facilitates adhesion to the endothelium and thus enables extravasation - the process is supported by mesenchymal-epithelial transition (MET)
ETM serves to improve migration properties
- The initially arising micrometastases can rest for years without growth and then, for example after "successful" therapy of the primary tumor, begin to grow as a late recurrence and develop into macrometastases.
Types of metastasis:
lymphogenic: metastasis in the nearest lymph node (filter station of the immune system) or along the lymphatic vessel
cavitary: e.g. in gastric and ovarian carcinoma as peritoneal carcinoma and in lung and breast carcinoma as pleural carcinoma
hematogenous: distribution through the blood vessel system
By now ...
✅ you are informed about the meaning of the microcirculation in tumor tissue
✅ you know the difference between the vascular system of tumor tissue and physiological tissue
✅ you know how tumor angiogenesis is induced
✅ you know how metastasis works
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See you soon!