The Inhibition of Vessel Co-Option as an Emerging Strategy for Cancer Therapy

Abstract

Vessel co-option (VCO) is a non-angiogenic mechanism of vascularization that has been associated to anti-angiogenic therapy. In VCO, cancer cells hijack the pre-existing blood vessels and use them to obtain oxygen and nutrients and invade adjacent tissue. Multiple primary tumors and metastases undergo VCO in highly vascularized tissues such as the lungs, liver or brain. VCO has been associated with a worse prognosis. The cellular and molecular mechanisms that undergo VCO are poorly understood. Recent studies have demonstrated that co-opted vessels show a quiescent phenotype in contrast to angiogenic tumor blood vessels. On the other hand, it is believed that during VCO, cancer cells are adhered to basement membrane from pre-existing blood vessels by using integrins, show enhanced motility and a mesenchymal phenotype. Other components of the tumor microenvironment (TME) such as extracellular matrix, immune cells or extracellular vesicles play important roles in vessel co-option maintenance. There are no strategies to inhibit VCO, and thus, to eliminate resistance to anti-angiogenic therapy. This review summarizes all the molecular mechanisms involved in vessel co-option analyzing the possible therapeutic strategies to inhibit this process.

Keywords: adhesion; angiogenesis; extracellular matrix; vessel co-option.

Figure 1

Tumor angiogenesis leads to non-functional blood vessels. Small tumors have an avascular growth, receiving nutrients and oxygen by diffusion. When they reach a certain size and the levels of pro-angiogenic factors (such as VEGF) are higher than the anti-angiogenic factors, an angiogenic switch takes place. VEGF signaling through its receptor VEGFR2 promotes endothelial cell proliferation, migration and survival to by the activation of multiple pathways, which lead to angiogenesis. Tumor blood vessels are poorly covered by pericytes and leaky leading to increased hypoxia. Hypoxia in solid tumors is also generated for the rapid growth of tumors that increase the oxygen demand that cannot be supplied [13]. Pericytes secrete Ang1, which binds with the Tie-2 receptor in endothelial cells. Ang 1 promotes the interaction between endothelial cells and pericytes to stabilize the new vessels’ structure. Nevertheless, the tumor vessels are not mature because the pericyte coverage is partial. Consequently, they have high permeability and are not functional resulting in a poor drug delivery and ineffective therapies. Created with BioRender.com, accessed on 8 January 2024.

Figure 2

Histological features of VCO vs. angiogenic tumors in the lungs. Healthy lung show type I and type II pneumocytes covering each alveoli. In the VCO alveolar growth pattern cancer cells grow to fill air spaces inside the alveoli. Lung parenchyma is preserved and pneumocytes and pre-existing blood vessels are in the same interface. In the VCO interstitial growth pattern, cancer cell growth in the alveolar wall compresses air spaces. In the perivascular cuffing growth pattern, cancer cells grow surrounding pulmonary big vessels. Schematics have been made using BioRender.com accessed on 8 January 2024.

Figure 3

VCO induces tumor hypoxia. Different mechanisms in VCO induce tumor hypoxia. During VCO, cancer cells hijack pre-existing blood vessels and compress them. This generates a decrease of blood flow that leads to hypoxia. At the same time, cancer cell proliferation increases oxygen demand, that the reduced blood flow cannot supply. This lead to a decrease of the oxygen levels in the TME. On the other hand, during VCO, the VEGF/VEGFR2 signaling pathway is downregulated, and this downregulation lead to an increase of MET signaling. MET activation activates hypoxia inducible factors, such as HIF1α.

Figure 4

Different strategies for VCO inhibition. (A) Inhibition of the adhesion between cancer cells and pre-existing blood vessels. Cancer cells growing by VCO are adhered to pre-existing blood vessels thanks to the participation of α1, α3 and β1 integrins or the L1CAM glycoprotein. For this reason, different molecules and antibodies that act as inhibitors and prevent tumor cell attachment to pre-existing blood vessels can be used to inhibit VCO. (B) Inhibition of ECM components. The compression of tumor blood vessels limits blood flow and oxygen distribution in the tumor microenvironment. Consequently, hypoxia induces changes in ECM since it favors the formation of LOX enzymes and MMPs involved in the colonization of new tumor cells and cell migration, respectively. In addition, secretion of HIF promotes the recruitment of CAFs that increase the stiffness of the extracellular matrix and favor tumor cell invasion. Finally, oxygen deprivation contributes to the release of immunosuppressive cells such as M2 macrophages and TGF-β that reduce the efficacy of the immune system. Thus, the study of inhibitors of HIF, LOX and MMPs (MMP2 and MMP14) may be an effective strategy to combat the harms of vascular co-opted tumors. (C) Inhibition of cell motility. In liver metastases with VCO, it has been shown that the Arp 2/3 complex promotes tumor cell migration by polymerization of actin filaments. Therefore, it is of interest to study the involvement of this complex in this type of tumor growth in other cancers and to find effective inhibitors to prevent VCO, since the use of shRNA has shown efficacy in experimental models with the HT29 cell line. (D) Modulation of tumor blood vessels. The inadequate blood flow that reaches tumor cells favors the generation of a hypoxic environment that promotes cancer cells to acquire an aggressive phenotype. For this reason, efforts are being made to develop therapies (vascular normalization and vascular promotion) that improve the functionality of tumor blood vessels and induce the generation of new vessels through the process of angiogenesis to increase the delivery of oxygen and drugs to the tumor, thus improving the efficacy of treatments. (E) Inhibition of epithelial–mesenchymal transition. It has been demonstrated the increased expression of EMT-related genes in colorectal metastases that co-opt tumor blood vessels. Furthermore, the use of anti-angiogenic agents in VCO tumors results in increased tumor invasiveness due to a shift of the cells towards a mesenchymal phenotype. Therefore, the use of inhibitors against genes involved in EMT transition such as SNAIL, ZEB and TWIST have shown efficacy in lung, brain, colorectal and breast tumors that can develop VCO growth. Figure created using BioRender.com accessed on 8 January 2024.