It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.The long-standing proposition that induction of chronic angiogenesis is a hallmark of cancer is now solidly grounded in a substantial body of research involving genetic and pharmacological perturbation of elements in the vascular regulatory circuitry. The 'angiogenic switch'1 is increasingly recognized as a rate-limiting secondary event in multistage carcinogenesis 2 , as documented in animal models of cancer and correlated in advanced pre malignant stages, as well as their malignant derivatives, in a growing list of human cancer types. That this acquired capability is functionally important for manifestation of the disease has been further validated by the approval of angiogenesis inhibitors as cancer therapeutics, most notably ones targeting the vascular endothelial growth factor (VEGF) pro-angiogenic signalling pathways 3 . The pioneers of the clinical proof-of-concept for angiogenesis inhibitors are bevacizumab (Avastin, Genentech/Roche), a ligand-trapping monoclonal antibody, and two kinase inhibitors (sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer)) targeting the VEGF receptor (VEGFR) tyrosine kinases, principally VEGFR2 (also known as KDR). Since March 2008, bevacizumab has been approved for treating patients with late-stage colon cancer, non-small-cell lung cancer and breast cancer, all in combination with chemotherapy. Sorafenib and sunitinib have both been approved for treating renal carcinoma, a highly vascularized (and angiogenic) tumour type. In addition, sunitinib has been approved for treating gastrointestinal stromal tumours, and sorafenib for hepatocel-lular carcinomas3 -6. Numerous ongoing clinical trials seek to expand the applications of each of these VEGF pathway inhibitors, and dozens of other angiogenesis inhibitors (many also targeting VEGF signalling) are being clinically evaluated (see Angiogenesis Inhibitors Therapy URL and clinical trials URLs in Further information). Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneration 7-9.Many of the demonstrable clinical benefits and side ef...

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.

SUMMARY Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.

Homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes develop normally, apoptosis, vascularization, and ossification are delayed, resulting in progressive lengthening of the growth plate to about eight times normal. After 3 weeks postnatal, aberrant apoptosis, vascularization, and ossification compensate to remodel the enlarged growth plate and ultimately produce an axial skeleton of normal appearance. Transplantation of wild-type bone marrow cells rescues vascularization and ossification in gelatinase B-null growth plates, indicating that these processes are mediated by gelatinase B-expressing cells of bone marrow origin, designated chondroclasts. Growth plates from gelatinase B-null mice in culture show a delayed release of an angiogenic activator, establishing a role for this proteinase in controlling angiogenesis.

Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition.

Blood vessels are composed of two interacting cell types. Endothelial cells form the inner lining of the vessel wall, and perivascular cells--referred to as pericytes, vascular smooth muscle cells or mural cells--envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyperdilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.

Development of hypoxic regions is an indicator of poor prognosis in many tumors. Here, we demonstrate that HIF1alpha, the direct effector of hypoxia, partly through increases in SDF1alpha, induces recruitment of bone marrow-derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+, and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP-9 activity of bone marrow-derived CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1alpha, SDF1alpha levels decrease, and fewer BM-derived cells are recruited to the tumors, decreasing MMP-9 and mobilization of VEGF. VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment.