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. 2010 Jan;1(1):12-25.
doi: 10.1177/1947601909356574.

Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates

Sonja Loges  1 , Thomas Schmidt, Peter Carmeliet
Affiliations

Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates

Sonja Loges et al. Genes Cancer. 2010 Jan.

Abstract

The concept of inhibiting tumor neovessels has taken the hurdle from the bench to the bedside and now represents an extra pillar of anticancer treatment VSports手机版. So far, anti-angiogenic therapy prolongs survival in the order of months in some settings while failing to induce a survival benefit in others, in part because of intrinsic refractoriness or evasive escape. This review provides an update on recent mechanisms via which tumor and stromal cells induce resistance and discusses recent evolutions in the (pre)clinical development of novel third-generation anti-angiogenic agents to overcome this problem. .

Keywords: angiogenesis; novel drug candidates; resistance V体育安卓版. .

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Conflict of interest statement

P V体育ios版. Carmeliet is named as inventor on patents, claiming subject matter that is partially based on the results described in this article. The patents are licensed/submitted, which may result in royalty payment to Peter Carmeliet.

"VSports注册入口" Figures

Figure 1.
Figure 1.
Principles of resistance against anti-angiogenic treatment. Upper left panel: cancer cells amplify angiogenic genes in their genome, which induces higher levels of gene expression, potentially requiring higher amounts of anti-angiogenic drugs. Upper right panel: tumors can switch between sprouting angiogenesis (tip cell of growing sprout in dark red), vasculogenesis (bone marrow derived, angiocompetent cells in purple), vessel co-option (tumor cells growing along a vessel in blue), and vascular mimicry (tumor cells lining vessels in blue) to ensure their nutrition. Lower right panel: tumors recruit a heterogeneous mixture of bone marrow–derived cells (purple), which confer resistance by secreting potent angiogenic and lymphangiogenic mediators such as vascular endothelial growth factor (VEGF) and VEGF-C. Lower left panel: within malignant tumors, tumor cells (blue) and stromal cells (yellow) express multiple pro-angiogenic factors, readily substituting for each other. Expression of alternative angiogenic proteins is even enhanced upon treatment with agents targeting VEGF (VEGF(R)Is).
Figure 2.
Figure 2.
Treatment-induced hypoxia mediates resistance against anti-angiogenic therapy at the interface between tumor and host. Hypoxia-induced mechanisms of tumor cell escape (left panel): increased upregulation of a plethora of angiogenic mediators, selection of cancer cells with enhanced resistance to chemo- and radiotherapy (in red), increased selection of intrinsically hypoxia-tolerant and pro-angiogenic cancer stem cells (CSCs, in yellow), and enhanced invasive properties of tumor cells. Host-related mechanisms of escape (right panel): hypoxia increases recruitment of endothelial progenitor cells (EPCs, green) and recruited bone marrow–derived circulating cells (RBCCs, green) toward the tumor vasculature, where they indirectly promote angiogenesis by secretion of angiogenic cytokines or, more rarely, directly integrate into blood vessels. Different subpopulations of myeloid cells, including tumor-associated macrophages (TAMs, brown), infiltrate tumors and mediate resistance by secreting tumor-promoting, angiogenic, and lymphangiogenic cytokines. Mesenchymal stem cells (MSCs, green) promote metastasis by secreting CCL5. Cancer-associated fibroblasts (CAFs, brown) are activated to support tumor growth and angiogenesis by fibroblast growth factors (FGFs), which are more abundant in hypoxia. Moreover, increased coverage with supporting pericytes (green) increases resistance toward agents targeting vascular endothelial growth factor (VEGF).
Figure 3.
Figure 3.
Alternative targets to overcome resistance. Upper left panel: anti–placental growth factor (PlGF) and anti–Bombina variegata (Bv) 8 inhibit tumor angiogenesis and at the same time infiltration of tumors with resistance-conferring myeloid cells. Upper right panel: targeting Notch regulatory pathways by anti–Deltalike ligand (Dll) 4 and γ-secretase inhibitors induces excessive sprouting of a leaky, dysfunctional vessel, leading to tumor hypoxia (hypoxic tumor region highlighted in blue). Lower right panel: induction of vessel normalization by inhibiting PHD2 improves vessel function and reduces hypoxia and metastasis. Lower left panel: molecules that were initially discovered to regulate axon guidance have emerged as important mediators of angiogenesis. Anti–Neuropilin 1 (Npn1) inhibits tumor growth and angiogenesis, and anti-Npn2 inhibits lymphangiogenesis.
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