The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

Abstract

Genetic and pathophysiologic criteria prearrange the uncontrolled growth of neoplastic cells that in turn initiates new vessel formation, which is prerequisite for further tumor growth and progression. This first endothelial lining is patchy, disordered in structure and thus, angiogenic tumor vessels were proven to be functionally inferior. As a result, tumors were characterized by areas with an apparent oversupply in addition to areas with an undersupply of vessels, which complicates an efficient administration of intravenous drugs in cancer therapy and might even lower the response e.g. of radiotherapy (RT) because of the inefficient oxygen supply. In addition to the vascular dysfunction, tumor blood vessels contribute to the tumor escape from immunity by the lack of response to inflammatory activation (endothelial anergy) and by repression of leukocyte adhesion molecule expression. However, tumor vessels can remodel by the association with and integration of pericytes and smooth muscle cells which stabilize these immature vessels resulting in normalization of the vascular structures. This normalization of the tumor vascular bed could improve the efficiency of previously established therapeutic approaches, such as chemo- or radiotherapy by a more homogenous drug and oxygen distribution, and/or by overcoming endothelial anergy. This review highlights the current investigations that take advantage of a proper vascular function for improving cancer therapy with a special focus on the endothelial-immune system interplay.

Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma

“…65 The findings of our study are timely as vascular normalization is quickly becoming an attractive therapeutic strategy. 31,66,67 Dual targeting of both ANG2 and VEGFA signaling has demonstrated efficacy in pre-clinical animal models of breast cancer, colon cancer, and glioblastoma. [68][69][70] ANG2 itself is an attractive therapeutic target as studies have shown that inhibition of ANG2 signaling decreases tumor growth and metastasis.…”

“…The tumor vasculature is a key mediator of lymphocyte exclusion whereby the vessels themselves can impede leukocyte tethering and subsequent extravasation into tumor tissues. 25,30,31 Due to the T cell exclusion observed in metastatic OS ( Figure 5), we focused our attention towards further investigating the relationship between vascular function and lymphocyte abundance. E-selectin, encoded by the SELE gene, is an endothelial cell adhesion molecule that facilitates leukocyte tethering and rolling on the vascular wall, the first step in [32][33][34] Whereas ICAM1 and PECAM1 can be expressed in both endothelial cells and tumor cells, SELE is expressed exclusively in endothelial cells and is transcriptionally upregulated in response to inflammation, thus serving as a marker of an activated and functional endothelium.…”

Cell adhesion in cancer: Beyond the migration of single cells

“…However, the endothelial cells that line these new vessels have lower than normal expression of endothelial adhesion molecules, such as intercellular adhesion molecules 1 and 2, vascular cell adhesion molecule 1, E-selectin, and CD34 (94). This endothelial anergy, characterized as unresponsiveness to inflammatory signaling, results in decreased adhesion of immune cells to the wall of the vessel, leading to reduced effector T-cell infiltration into the tumor, which is a key mechanism of immune evasion of solid malignancies (95).…”

Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor–stroma interactions

“…Herein, the tumor microenvironment is increasingly recognized not just as a growth-supporting tumor compartment but as a key determinant of radiation therapy (RT) resistance [13][14][15][16] . Among the cell types within the tumor-stroma, ECs were shown to be critical determinants of the radiation response of tumors 9,[17][18][19][20] . IR exposure induced acute vascular damage and EC apoptosis, leading to severe EC loss finally resulting in vascular dysfunction 17,[20][21][22] .…”

“…Among the cell types within the tumor-stroma, ECs were shown to be critical determinants of the radiation response of tumors 9,[17][18][19][20] . IR exposure induced acute vascular damage and EC apoptosis, leading to severe EC loss finally resulting in vascular dysfunction 17,[20][21][22] . Mechanistically, the p38 MAPK signaling pathway is essential for the EC response to stress stimuli including IR 23 .…”