Rinat Abramovitch

Stimulation of tumour growth by wound-derived growth factors.

SummaryThe goal of this work was to determine the molecular basis for the induction of tumour vascularization and progression by injury. Magnetic resonance imaging (MRI) studies demonstrated that administration of wound fluid derived from cutaneous injuries in pigs reduced the lag for vascularization and initiation of growth of C6 glioma spheroids, implanted in nude mice, and accelerated tumour doubling time. The former effect can be attributed to the angiogenic capacity of wound fluid as detected in vivo by MRI, and in vitro in promoting endothelial cell proliferation. The latter effect, namely the induced rate of tumour growth, is consistent with the angiogenic activity of wound fluid as well as with the finding that wound fluid was directly mitogenic to the tumour cells, and accelerated growth of C6 glioma in spheroid culture. Of the multiple growth factors present in wound fluid, two key factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and platelet-derived growth factor (PDGF), were identified as the dominant mitogens for C6 glioma, and inhibition of their activity using specific neutralizing antibodies suppressed the mitogenic effect of wound fluid on DNA synthesis in C6 glioma. This study suggests that the stimulatory effect of injury on tumour progression can possibly be attenuated by therapeutic targeting directed against a limited number of specific growth factors.

Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle

The preovulatory follicle provides a unique physiological example of rapid growth accompanied by neovascularization, two processes that are generally characteristic of pathologies such as wound repair or malignancy. During the hours preceding ovulation, follicular growth is accompanied by elevated levels of messenger RNA for vascular endothelial growth factor (VEGF). Angiogenic activity, mediated by VEGF, is manifested in the peripheral blood vessels surrounding the follicle, that show capillary sprouting and increased vascular permeability. Following ovulation, rapid infiltration of capillaries through the follicular wall is essential for the formation of the corpus luteum. In this review we compare the preovulatory follicle with a popular model of avascular solid tumour growth, namely the multicellular tumour spheroid, in particular the role of hypoxic stress in the regulation of angiogenesis in both systems.

Intercellular communication between vascular smooth muscle and endothelial cells mediated by heparin-binding epidermal growth factor-like growth factor and vascular endothelial growth factor

Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), a potent mitogen and migration factor for vascular smooth muscle cells (SMC), promoted neovascularization in vivo in the rabbit cornea. MRI demonstrated quantitatively the angiogenic effect of HB‐EGF when introduced subcutaneously into nude mice. HB‐EGF is not directly mitogenic to endothelial cells but it induced the migration of bovine endothelial cells and release of endothelial cell mitogenic activity from bovine vascular SMC. This mitogenic activity was specifically blocked by neutralizing anti‐vascular endothelial growth factor (VEGF) antibodies. In contrast, EGF or transforming growth factor‐α (TGF‐α) had almost no effect on release of endothelial mitogenicity from SMC. In addition, RT‐PCR analysis demonstrated that VEGF165 mRNA levels were increased in vascular SMC 4–10‐fold by 0.35–2 nM of HB‐EGF, respectively. Our data suggest that HB‐EGF, as a mediator of intercellular communication, may play a new important role in supporting wound healing, tumor progression and atherosclerosis by stimulating angiogenesis.

Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI

We show here, using high-resolution magnetic resonance imaging, that injured tissue provides a favourable milieu for the neovascularization and growth of C6 glioma spheroids, implanted subcutaneously in nude mice. Moreover, the presence of micro-tumours in an injured tissue inhibited the healing process, leaving an open persistent wound. In correlation with the induced angiogenesis of implanted spheroids in the presence of proximal wounds, a shorter lag period was observed for initiation of tumour growth. This effect was restricted spatially and was observed only for wounds within 5 mm from the tumour. In such proximal wounds, angiogenesis was enhanced in the first days after injury, and vessel regression, which normally starts 4 days after injury, did not occur. Injury causing interference to tumour perfusion promoted tumour vascularization and growth even for more remote incisions, possibly by activating stress-induced angiogenesis. The kinetics of vascularization and growth of these wound-tumour systems sheds light on the clinical observations of increased probability of metastatic recurrence and stimulated regrowth of residual tumour in the site of surgical intervention. High-resolution magnetic resonance imaging could detect the aberrant angiogenic activity of these tumour-wound systems as early as 1 week after injury.

Mapping Neovascularization and Antineovascularization Therapy

The switch of tumors from avascular to the vascular phase and the onset of tumor angiogenesis mark a critical checkpoint in tumor progression. Avascular tumor dormancy can sometimes extend over many years, while upon vascularization, tumors show increased invasiveness, elevated metastatic potential and significantly worse prognosis (Weidner and Folkman, 1996). Regulation of the transition to the vascular phase depends on the balance between the production of promoters and inhibitors of angiogenesis (Hanahan and Folkman, 1996). The goal of our work was to define physiological scenarios which perturb this balance and can thus drive angiogenesis to previously dormant tumors. Such mechanisms that promote angiogenesis may explain epidemiological observations regarding age specific probabilities of certain tumors, environmental effects and the effects of trauma on tumor growth. In order to follow angiogenesis quantitatively, we developed an experimental system that relies on detection of vessel density by magnetic resonance imaging (MRI).