Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice

Abstract

Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b + myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells

“…Angiogenesis is the subsequent process by which these vessels take shape from these existing blood vessels by 'sprouting' of endothelial cells thus expanding the vascular tree. 31,32 For tumour mass survival and continuous growth, tumours must develop a blood vessel network to help carry oxygenated blood, nutrients, etc. to the cancer cells within the tumour mass.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…On the other hand, the relative abundance of immunosuppressive T‐regulatory cells (Tregs) (Bates et al., 2006; Pages et al., 2010) or CD4 + effector T‐cells (Denardo et al., 2011; Kohrt et al., 2005; Zhou et al., 2009) can be prognostic of comparatively poor outcome, as can the abundance of various myeloid cell types, including macrophages, neutrophils and immature myeloid cells (Qian and Pollard, 2010; Steidl et al., 2011; Zhou et al., 2009), a subset of which are referred to as myeloid‐derived suppressor cells on account of their ability to inhibit T‐cell functions (Sica and Bronte, 2007). Furthermore, studies in mouse models of cancer have revealed that profuse myeloid cell infiltration correlates with resistance to antiangiogenic therapies targeting the VEGF‐signaling axis (Bergers and Hanahan, 2008; Ferrara, 2010; Squadrito and De Palma, 2011), or accelerated tumor re‐growth following local tumor irradiation (Ahn and Brown, 2008; Kioi et al., 2010; Kozin et al., 2010). Additionally, there is considerable phenotypic and functional heterogeneity among macrophage and neutrophil subtypes, most simply reflected in the amalgam of conventionally or alternatively activated macrophages found in tumors, as well as in inflamed or healing tissues (Biswas and Mantovani, 2010; Coffelt et al., 2010; Gordon and Martinez, 2010; Nucera et al., 2011; Piccard et al., 2011).…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…In mice, radiotherapy-induced TAM infiltration is mainly attributed to radiation-induced hypoxia and the subsequent surge in hypoxia-regulated chemokines, such as CXCL12 [90,93]. Monocytes and macrophages expressing TIE2 -the receptor for Angiopoietins 1 and 2 -are highly receptive to increased hypoxia and CXCL12 levels [90,93,94], and TIE2-expressing monocytes/macrophages 10 have a profound ability to counteract hypoxia through the induction of angiogenesis [95].…”

“…In mice, radiotherapy-induced TAM infiltration is mainly attributed to radiation-induced hypoxia and the subsequent surge in hypoxia-regulated chemokines, such as CXCL12 [90,93]. Monocytes and macrophages expressing TIE2 -the receptor for Angiopoietins 1 and 2 -are highly receptive to increased hypoxia and CXCL12 levels [90,93,94], and TIE2-expressing monocytes/macrophages 10 have a profound ability to counteract hypoxia through the induction of angiogenesis [95]. As one may predict, neutralizing CXCL12 or blocking its receptor, CXCR4, to prevent TAM accumulation further delays tumor progression when combined with radiotherapy in orthotopic syngeneic and xenograft models of glioblastoma [90], as well as subcutaneous xenografts of lung carcinoma and syngeneic mammary tumors [93].…”

“…Monocytes and macrophages expressing TIE2 -the receptor for Angiopoietins 1 and 2 -are highly receptive to increased hypoxia and CXCL12 levels [90,93,94], and TIE2-expressing monocytes/macrophages 10 have a profound ability to counteract hypoxia through the induction of angiogenesis [95]. As one may predict, neutralizing CXCL12 or blocking its receptor, CXCR4, to prevent TAM accumulation further delays tumor progression when combined with radiotherapy in orthotopic syngeneic and xenograft models of glioblastoma [90], as well as subcutaneous xenografts of lung carcinoma and syngeneic mammary tumors [93].When TAMs are depleted in various subcutaneous transplantable and xenograft models by targeting all CD11b + cells, the inhibitory effects of radiation on tumor growth and angiogenesis are augmented [88,89]. This result may be largely explained by the contribution of MMP9 by CD11b + cells that drives tumor regrowth through vasculogenesis [88,89].…”