Tumor-associated endothelial cell

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A visualization of tumor-associated blood vessels in the human breast

Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. [1] 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. [2] [3] [4] There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors. [3]

Contents

Abnormal morphology

Tumor endothelial cells (TECs) have been documented to demonstrate abnormal morphological characteristics such as ragged margins and irregular cytoplasmic projections. [1] 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. [5] In addition to this, TECs are showing distinct molecular signature which clearly separates them from physiological endothelial cells. [2] The tumor endothelium is often described as mosaic due to its aberrant expression of traditional endothelial cell markers (CD31 and CD105), [2] supporting the existence of irregular gaps between endothelial cells. [6] 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. [1]

Causes of abnormalities

Many tumors are characterized by high expression of vascular endothelial growth factor (VEGF), which is a strong vasodilator. VEGF has been indicated to stimulate sprouting and tip branching in endothelial cells, leading to defective endothelial monolayers. [7] Research supports that compression of tumor vessels by surrounding tumor cells results in mechanical tension and changes in blood flow. [8] It has been suggested that these flow-mediated changes cause abnormal expression of transcription factors which promotes aberrant endothelial morphology, size, and differentiation. [9]

Smaller capillaries are often surrounded by supporting pericytes which help with vessel stability. [10] 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. [11] Lower quantity of pericytes surrounding the tumor-associated endothelium has been associated with blood vessel instability and leakiness. [12]

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. [13] These cellular openings contribute to tumor vessel "leakiness", potentially allowing the entry and delivery of therapeutic agents to tumor sites. [14] [5] For many tumors, it has been discovered associated endothelial cells have significantly increased permeability. [15] [16]

Enhanced permeability and retention (EPR) effect

Illustration of the Enhanced Permeation and Retention (EPR) effect of macromolecular structures as drug delivery systems in malignant tissue. Enhanced Permeation and Retention (EPR) effect.svg
Illustration of the Enhanced Permeation and Retention (EPR) effect of macromolecular structures as drug delivery systems in malignant tissue.

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. [17] This observation has been termed the enhanced permeability and retention (EPR) effect and has been exploited for cancer nano-therapeutics. [18] 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. [19] Tumor type, size, and location affect the nature of the surrounding vasculature and stroma and contribute to this heterogeneity in EPR effect. [19]

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. [20] The branching patterning of tumor-associated endothelial cells has been implicated in the initiation of angiogenesis. [21] Dr. Judah Folkman played an important role in studying the role of angiogenesis in promoting tumor growth. [22] [23] He identified tumor's response to hypoxia as a leading contributor to angiogenesis and cancer growth. [22]

Angiogenesis was originally introduced as a Hallmark of Cancer based on assumptions that the underlying processes were similar amongst different tumor types. [24] 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. [2] [25] 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. [2] [25]

Angiogenesis inhibitors

Various angiogenesis inhibitors have been developed to interfere with different steps in the process. [26] Bevacizumab (Avastin) is a monoclonal antibody that binds to VEGF, preventing the stimulation of the VEGF receptor. [27] Sorafenib 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. [28] 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. [26]

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, inhibiting the effectiveness of immune therapies. [29] 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. [30]

Metastasis

The vasculature can promote metastasis by capturing cancer cells at their primary sites and providing for their delivery to secondary organs. [31] 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. [2] [31] Additionally, angiogenesis is intimately linked to metastasis, as delivery of nutrients and oxygen through blood vessels is required for invasive tumor growth and spread. [32]

See also

Related Research Articles

Angiogenesis Blood vessel formation, when new vessels emerge from existing vessels

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. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Endothelium Layer of cells that lining inner surface of blood vessels

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 wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Pericyte Cells associated with capillary linings

Pericytes 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 capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. Pericytes help to maintain homeostatic and hemostatic functions in the brain, one of the organs with higher pericyte coverage, and also sustain the blood–brain barrier. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes have been postulated to regulate capillary blood flow and the clearance and phagocytosis of cellular debris in vitro. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier.

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, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

The enhanced permeability and retention (EPR) effect is a controversial concept by which molecules of certain sizes tend to accumulate in tumor tissue much more than they do in normal tissues. The general explanation that is given for this phenomenon is that, in order for tumor cells to grow quickly, they must stimulate the production of blood vessels. VEGF and other growth factors are involved in cancer angiogenesis. Tumor cell aggregates as small as 150–200 μm, start to become dependent on blood supply carried out by neovasculature for their nutritional and oxygen supply. These newly formed tumor vessels are usually abnormal in form and architecture. They are poorly aligned defective endothelial cells with wide fenestrations, lacking a smooth muscle layer, or innervation with a wider lumen, and impaired functional receptors for angiotensin II. Furthermore, tumor tissues usually lack effective lymphatic drainage. All of these factors lead to abnormal molecular and fluid transport dynamics, especially for macromolecular drugs. This phenomenon is referred to as the "enhanced permeability and retention (EPR) effect" of macromolecules and lipids in solid tumors. The EPR effect is further enhanced by many pathophysiological factors involved in enhancement of the extravasation of macromolecules in solid tumor tissues. For instance, bradykinin, nitric oxide / peroxynitrite, prostaglandins, vascular permeability factor, tumor necrosis factor and others. One factor that leads to the increased retention is the lack of lymphatics around the tumor region which would filter out such particles under normal conditions.

Endothelial stem cell Stem cell in bone marrow that gives rise to endothelial cells

Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The lymphatic vessels include things such as arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells

E-selectin

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

Angiopoietin Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

VEGF receptor

VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.

Endothelial progenitor cell is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation. Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research.

VE-cadherin

Cadherin 5, type 2 or VE-cadherin also known as CD144, is a type of cadherin. It is encoded by the human gene CDH5.

Vascular endothelial growth factor A Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteases (MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Tumstatin is a protein fragment cleaved from collagen that serves as both an antiangiogenic and proapoptotic agent. It has similar function to canstatin, endostatin, restin, and arresten, which also affect angiogenesis. Angiogenesis is the growth of new blood vessels from pre-existing blood vessels, and is important in tumor growth and metastasis. Angiogenesis is stimulated by many growth factors, the most prevalent of which is vascular endothelial growth factor (VEGF).

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Tumor microenvironment

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Vasculogenic mimicry is the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumour cells. This process differs from angiogenesis in that it occurs de novo without the presence of endothelial cells. It was first described in uveal melanomas by Maniotis et al. in 1999. There are two main types of vasculogenic mimicry: tubular and patterned. The former is morphologically similar to normal blood vessels, whereas the latter is visibly different although capable of undergoing anastomosis with blood vessels.

A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.

The host response to cancer therapy is defined as a physiological response of the non-malignant cells of the body to a specific cancer therapy. The response is therapy-specific, occurring independently of cancer type or stage.

References

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