Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated

blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...

s 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 Morphology, from the Greek and meaning "study of shape", may refer to: Disciplines * Morphology (archaeology), study of the shapes or forms of artifacts * Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies ...

, 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 The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

to destroy tumors.

Abnormal morphology

Tumor endothelial cells (TECs) 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 junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

s 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 (

CD31 Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the ''PECAM1'' gene found on chromosome17q23.3. PECAM-1 plays a key role in removing aged neutrop ...

and

CD105 Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefor ...

), 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 Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF), 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

pericyte Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...

s which help with vessel stability. Loss of pericyte growth factor (PDGFB) 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 Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

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

Enhanced Permeation and Retention (EPR) effect

The increased permeability of tumor-associated endothelial cells permits

macromolecule A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

s 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 Lymph (from Latin, , meaning "water") is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to ...

infiltration. This observation has been termed the

enhanced permeability and retention (EPR) effect ''Enhanced'' is a 2019 Canadian-Japanese action film produced, written and directed by James Mark. The film premiered at the 2019 Toronto After Dark Film Festival. Plot A sinister government organization hunts down mutants, and one of such is a ...

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 Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, 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.

Angiogenesis inhibitors

Various angiogenesis inhibitors have been developed to interfere with different steps in the process.

Bevacizumab Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, l ...

(

Avastin Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (Intravenous therapy, intravenous) and use ...

) is a monoclonal antibody that binds to VEGF, preventing the stimulation of the VEGF receptor.

Sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...

and sutinib are additional angiogenesis inhibitors that bind and block receptors on endothelial cells that have important roles in downstream pathways contributing to angiogenesis progression. An extensive amount of other compounds targeted towards halting angiogenesis are either currently in preclinical development, undergoing clinical trials, or in the process of getting approved by the

United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

Immune suppression

Immune therapies depend heavily on the abilities of effector lymphocytes to infiltrate tumors, and the tumor endothelium is a known crucial regulator of T-cell trafficking. The tumor-associated endothelium has been found to be able to function as an immune barrier to

T-cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

, inhibiting the effectiveness of immune therapies. These tumor-associated endothelial cells have been found to over-express the endothelin B receptor, which suppresses T-cell adhesion and targeting to tumors upon activation by ET-1.

Metastasis

The vasculature can promote

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

by capturing cancer cells at their primary sites and providing for their delivery to secondary organs. These tumor-associated endothelial cells can also release factors and supply nutrients that promote the growth of the primary tumor mass and its aggressive spread. Additionally, angiogenesis is intimately linked to metastasis, as delivery of nutrients and oxygen through blood vessels is required for invasive tumor growth and spread.

References

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