Angiocrine endothelium: from physiology to cancer

Abstract

The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.

Keywords: Angiocrine; Angiogenesis; Cancer; Cancer microenvironment; Endothelium.

Fig. 1

The angiocrine and angiogenic switch during tumor progression. Vascular endothelial cells are capable of enhancing tumor growth and migration by secreting several cytokines and growth factors or activating the so-called angiocrine switch (bottom). This switch is activated by signals directed to ECs from their surrounding tumor cells. As a result, the activated ECs increase the production of angiocrine factors that confer many growth advantages to tumor cells. The angiocrine factors may be in the form of transmembrane ligands, secretory cytokines, or microparticle-packaged factors. There is evidence that activated ECs trough their interaction with tumor cells demonstrate some degree of plasticity toward a mesenchymal phenotype with enhanced tumor promoting potential

Fig. 2

The role of angiocrine endothelium in promoting tumorigenicity. ECs were initially known for their role in tumor angiogenesis. Emerging evidence shows an angiocrine role for tumor endothelium in inducing tumor growth and survival advantages through production of angiocrine factors. Several angiocrine factors such as VEGF, bFGF, IL-6, IL-8, TGFβ, PDGFβ, Jag1, and Endothelin, have been shown to enhance tumor cell proliferation. Also, a role for angiocrine factors is implicated in increased proliferation of cancer stem and progenitor cells in brain tumor (BDNF, PEDF, BMP2, and BMP4), head and neck cancer (EGF), and breast cancer (Jag1). Recent evidence demonstrates the participation of angiocrine endothelium in tumor immune tolerance. Angiocrine molecules such as ICAM-1, VCAM, and Selectin regulate the transmigration of lymphocytes through the lymphatic vessels. Endothelial bFGF plays a role in stimulation of leukocyte infiltration. Some secretory chemokine (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) affect T cell infiltration to the tumor site. ECs are also capable of over-expressing specific molecules such as ET_BR to provide a barrier for tumor-infiltrating lymphocytes. Additional mechanisms include escape from immune response regulated by Tim-3 or FasL. A recent angiocrine function for endothelial-derived thrombospondin-1 is defined in induction of tumor dormancy. Besides, endothelial FGF2 is capable of triggering resistance of anti-angiogenic drugs through activation of FGF2/FGFR1 loop. Quite notably, some angiocrine elements may have multiple functions in tumor expansion. Table 1 provides distinct functional information for the viewers