Antiangiogenesis in the treatment of skin cancer

Angiogenesis is the formation of new capillary blood vessels from existing vasculature. Cancers are dependent upon angiogenesis for their growth. Inhibition of angiogenesis can slow, halt, or regress tumors. Angiogenesis inhibition is now validated for the treatment of cancer using a variety of approved biologic, small molecule, multitargeting, and immunomodulatory agents. In the skin, strategies to inhibit angiogenesis-signaling pathways include blockade of COX-2, m-TOR, sonic hedgehog, growth factor receptor activation, and activation of Toll-like receptors (TLR). The agent with the most clinical experience as a topical antiangiogenic therapy is imiquimod. Imiquimod is a TLR agonist, with immune response modifying properties that also stimulates antiangiogenic cytokines, downregulates the expression of proangiogenic factors, upregulates the expression of endogenous inhibitors, and induces endothelial cell apoptosis. By titrating its dosing for angiogenesis inhibitory activity and not for gross inflammation, imiquimod can be applied in an efficacious and well-tolerated fashion to treat skin cancer.

Judah Folkman's pioneering work in tumor angiogenesis beginning in the 1970s established the field of angiogenesis research. (1) Since then, an enormous body of angiogenesis research has elucidated the growth control mechanisms of the microcirculation, yielding new insights into the critical role of new blood vessel growth in both physiological and pathological conditions.

All solid tumors are dependent upon angiogenesis to grow beyond a few millimeters in diameter. (3) Antiangiogenic therapy for cancer stems from a large body of experimental evidence showing that inhibition of angiogenesis can slow, halt, or regress tumors. Unlike cytotoxic chemotherapy and ionizing radiation, antiangiogenic therapy does not directly kill tumor cells but instead targets the vasculature supporting tumor growth, resulting in a cytostatic effect. This approach represents a paradigm shift for cancer treatment. Clinical benefits of antiangiogenic therapy include prolonged survival, disease stabilization, and improved quality of life, and can often be achieved with less debilitating toxicities than conventional therapies.

Angiogenesis in the Skin

Angiogenesis, the formation of new capillary blood vessels from the existing vasculature, is a tightly regulated physiological process. Under normal circumstances, vascular endothelial cells comprising blood vessels are quiescent and have one of the lowest mitotic rates in the body. (3) This non-proliferating state is governed by the balancing effects of endogenous stimulators and inhibitors of angiogenesis present in healthy tissue. Positive regulators of angiogenesis (proangiogenenic) include fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF; sometimes called vascular permeability factor), platelet-derived growth factor (PDGF), interleukin-8 (IL-8), and more than 30 other proteins. Endogenous angiogenesis inhibitors include endostatin, tumstatin, tissue inhibitors of matrix metalloproteinases (TIMPs), interferons (IFN-[alpha], -[beta], -[gamma]), interleukins (IL-10, IL-12, IL-18), and thrombospondins (TSP-1, TSP-2), among other factors.

Pathological angiogenesis, typically defined as aberrant or uncontrolled angiogenesis underlying a disease, occurs in a number of skin conditions. The epidermis is an avascular tissue layer separated from underlying dermal capillaries by the basement membrane. Viable epidermal cells are located within 100 to 150 [micro]m from vessels, the diffusion distance of oxygen. Beyond this zone, epidermal cells undergo keratinization and ultimately die and slough. Tumor cells in benign and malignant skin conditions are also subject to growth restriction defined by limits of oxygen diffusion. Unlike normal tissues, however, growing tumors release high concentrations of proangiogenic growth factors that induce capillary growth and override this control mechanism. Tumors can also upregulate growth factor production from host stroma, furthering the angiogenic process.

Skin Cancers

Like all solid malignancies, cancers occurring in skin are highly angiogenic. Vascular tumors of the skin, such as Kaposi's sarcoma, hemangioma of infancy, pyogenic granuloma, and angiosarcoma, are composed of proliferating cells of endothelial origin and are also angiogenesis-dependent. (4,5) Hemangiomas were the first human tumors to be successfully treated with antiangiogenic therapy using interferon-[beta]-2a, based on the recognition that they overexpress angiogenesis stimulators (FGF-2, VEGF) during the proliferative phase. (6,7) Conversely, during their involutional phase, endogenous angiogenesis inhibitors (tissue inhibitor of metalloproteinase-1 [TIMP-1], interferon-[beta] [IFN-[beta]]) are upregulated. (8)

Benign growths, such as warts, are also angiogenic in nature. (9-12) Increasing vascularity is observed between HPV-negative and HPV-positive warts; pinpoint hemorrhagic capillaries are a gross manifestation of the neovascularization that accompany wart growth and persistence. (9) Further, it has been shown that other HPV-associated lesions exhibit increased microvessel density during the transformation of intraepithelial neoplasia to anal carcinoma and from cervical dysplasia to cervical carcinoma.