Tumor-associated endothelial cell
Tumor-associated endothelial cells or tumor endothelial cells refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.
Abnormal morphology
Tumor endothelial cells have been documented to demonstrate abnormal morphological characteristics such as ragged margins and irregular cytoplasmic projections. In normal blood vessels, it is known that endothelial cells form regular monolayers with tight junctions without overlap, but TECs create disorganized and loosely connected monolayers, often branching and extending across the lumen to overlap with their neighbors. In addition to this, TECs are showing distinct molecular signature which clearly separates them from physiological endothelial cells. The tumor endothelium is often described as mosaic due to its aberrant expression of traditional endothelial cell markers, supporting the existence of irregular gaps between endothelial cells. At a more macro level, beyond the observation of small intercellular openings between nearby TECs, larger gaps in the walls of tumor blood vessels have been described.Causes of abnormalities
Many tumors are characterized by high expression of vascular endothelial growth factor, which is a strong vasodilator. VEGF has been indicated to stimulate sprouting and tip branching in endothelial cells, leading to defective endothelial monolayers. Research supports that compression of tumor vessels by surrounding tumor cells results in mechanical tension and changes in blood flow. It has been suggested that these flow-mediated changes cause abnormal expression of transcription factors which promotes aberrant endothelial morphology, size, and differentiation.Smaller capillaries are often surrounded by supporting pericytes which help with vessel stability. Loss of pericyte growth factor and its receptor on endothelial cells are molecular-level changes that can account for this abnormal loss in pericyte support. Lower quantity of pericytes surrounding the tumor-associated endothelium has been associated with blood vessel instability and leakiness.
Abnormal function
Blood vessel leakiness
Where these branched tumor-associated endothelial cells form small gaps in the blood vessel wall, erythrocytes often pool and form blood lakes. These cellular openings contribute to tumor vessel "leakiness", potentially allowing the entry and delivery of therapeutic agents to tumor sites. For many tumors, it has been discovered associated endothelial cells have significantly increased permeability.Enhanced permeability and retention (EPR) effect
The increased permeability of tumor-associated endothelial cells permits macromolecules to leave the blood system and directly enter the tumor interstitial space. There is also a retention effect that allows these macromolecules to stay at tumor sites due to the suppression of lymphatic infiltration. This observation has been termed the enhanced permeability and retention (EPR) effect and has been exploited for cancer nano-therapeutics. Unfortunately the effectiveness of this mechanism for drug nano-carriers remains inconsistent due to the heterogeneity of this EPR effect within and amongst different tumors. Tumor type, size, and location affect the nature of the surrounding vasculature and stroma and contribute to this heterogeneity in EPR effect.Roles in tumor progression
Angiogenesis
The idea of tumors promoting angiogenesis, or the process of forming new blood vessels, has been around since the discovery of VEGF in 1989. The branching patterning of tumor-associated endothelial cells has been implicated in the initiation of angiogenesis. Dr. Judah Folkman played an important role in studying the role of angiogenesis in promoting tumor growth. He identified tumor's response to hypoxia as a leading contributor to angiogenesis and cancer growth.Angiogenesis was originally introduced as a Hallmark of Cancer based on assumptions that the underlying processes were similar amongst different tumor types. However, there are now multiple studies that illustrate the complexity behind these previous simple conceptions of angiogenesis, indicating that the way cancer cells interact with and co-opt new blood vessel growth varies amongst cancer types and must be studied. This must be studied in order to improve clinical design strategy and select for patients with tumors that are more likely to benefit from anti-angiogenic drugs.