El cáncer se origina por una pérdida de control del crecimiento normal. En los tejidos normales, las tasas de crecimiento de nuevas células y la muerte de células viejas se mantienen en balance. En el caso del cáncer, este balance se altera. Esta alteración puede ocurrir como resultado de un crecimiento celular descontrolado o de la pérdida de una habilidad de la célula de someterse a suicidio celular mediante un proceso conocido como “apoptosis”. La apoptosis o “suicidio celular”, es el mecanismo mediante el cual las células viejas o dañadas normalmente se autodestruyen.
Los cánceres son capaces de diseminarse a través de todo el cuerpo mediante dos mecanismos: invasión y metástasis. La invasión se refiere a la migración y penetración directas de las células cancerosas en los tejidos vecinos. La metástasis se refiere a la habilidad de las células cancerosas para penetrar dentro de los vasos linfáticos y sanguíneos, circular a través del torrente sanguíneo y después invadir los tejidos normales en otras partes del cuerpo.
All cancers are similar in that the different diseases will all have these basic characteristics.
The primary endpoint of the analysis was disease free survival (DFS). There was both a strong statistically significant absolute advantage for trastuzumab (8% at 3 years), and also relative advantage (hazard ratio 0.48). This is a 52% reduction in recurrence and mortality events.
Induction of angiogenesis is essential for rapid tumor growth. In the absence of a vasculature, tumors remain small and dormant, approximately 1 to 2 mm in diameter. Small tumors acquire the ability to stimulate angiogenesis—turning the “angiogenic switch” on—through upregulating key proangiogenic factors such as VEGF and downregulating antiangiogenic factors such as thrombospondin 1. By inducing angiogenesis, small tumors acquire access to a blood supply, facilitating tumor growth and metastasis. Angiogenesis is important for the supply of oxygen, nutrients, growth factors/hormones, proteolytic enzymes, influences on hemostatic factors that control the coagulation and fibrinolytic system, and the dissemination of tumor cells to distal sites. One of the hallmarks of cancer is a “switch” to an angiogenic phenotpye where proangiogenic mechanisms overwhelm or circumvent negative regulators of angiogenesis Increased tumor vascularization and expression of proangiogenic factors have been associated with advanced tumor stages Activation of the VEGF/VEGF-receptor triggers multiple signaling networks that result in endothelial survival, mitogenesis, migration and differentiation, and vascular permeability and mobilization of endothelial progenitor cells from the bone marrow into the peripheral circulation VEGF induces increases in vessel permeability leads to deposition of proteins in the interstitium that facilitate angiogenesis.
Tumor blood vessels are molecularly and morphologically distinct from normal blood vessels. Normal blood vessels have specific features. Maturation factors are present. Endothelial cells are less dependent on growth factors for survival. Vessels are not leaky and permeable. Vessels have supporting pericytes. Expression of specific integrins is reduced. Normal blood vessels are organized with regularized structures. Tumor blood vessels Are more dependent on growth factors for endothelial cell survival. Are very leaky and fragile, prone to rupture and bleeding. Lack regular coverage by supporting pericytes. Preferentially express specific integrins on their surface. Are disorganized, twisted, and have variable pressure, resulting in uneven delivery of nutrients and oxygen to tumors.
VEGF plays a key role in the regulation of angiogenesis.1 Angiogenesis, the growth of blood vessels from existing vessels, is an important feature of tumor growth. Tumors begin to overexpress proangiogenic signals, such as VEGF — a process known as the “angiogenic switch” — in response to a multitude of stimuli.2 Many environmental factors, including hypoxia and low pH, stimulate the expression of VEGF.1 Hormones (eg, progesterone, estrogen), growth factors (eg, endothelial growth factor [EGF], transforming growth factor–beta [TGF-], basic fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], insulin-like growth factor [IGF]-1), and cytokines (eg, interleukin [IL]1, IL-6) also stimulate VEGF expression.1 In addition to exogenous factors, many tumorigenic mutations lead to VEGF upregulation. This can include mutations in cellular oncogenes, such as src, ras, and bcr-abl.1,3 Mutations in tumor suppressor genes such as p53, p73, and vHL also lead to upregulation of VEGF.1 VEGF then binds and activates its receptors, stimulating signaling cascades, involving phospholipase C, the nonreceptor tyrosine kinase src, phosphatidylinositol-3-kinase, and ras guanosine triphosphatase (GTP-ase)–activating protein.4 Downstream signaling events lead to inhibition of apoptosis, stimulation of mitosis, and cytoskeletal changes associated with motility and vascular permeability.4 Avastin is a recombinant humanized monoclonal antibody of the IgG1 isotype that binds VEGF.5 As a humanized antibody, Avastin is less likely to produce an immunogenic response compared with chimeric antibodies.6 Avastin binds to all isoforms of VEGF (VEGF-A) with high specificity and affinity resulting in potent VEGF-neutralizing activity.5 At least 4 different VEGF isoforms, with different molecular weights (206, 189, 165, and 121 kD) and heparin-binding properties, are created by alternative splicing of the VEGF-A gene.4 Once bound, Avastin prevents VEGF interactions with its cognate receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR), on the surface of endothelial cells, inhibiting VEGF-stimulated downstream signaling events.5 The estimated half-life of Avastin is about 20 days (with a range of 11 to 50 days).7 Avastin, a humanized monoclonal antibody, binds to VEGF, the most potent and predominant proangiogenic signal.