ABSTRACT
Solid tumors are thought to arise from small nodes of cells (which are typically somatic stem cells, as recently suggest in [240]) that have undergone genetic mutations and/or epigenetic alterations. They are able to escape from DNA repair mechanisms and to cause abnormal growth regulatory mechanisms [7, 297], surviving and evolving even under extreme conditions, e.g., hypoxia and acidosis [155]. Such primary malignant colonies go through a relatively simple, avascular stage of growth, with nutrient and growth factor supply by diffusion from the local microenvironment [7, 275, 401]. However, a further search of available quantities of critical substrates results in a subsequent aggressive phase, with the invasion of the surrounding tissue [7, 47]. In particular, as reproduced in Figure 8.1, a part of the malignant mass remains densely packed, while a number of isolated cells detach and begin to invade the neighboring spaces. These individuals are less adhesive, highly mobile and metabolically active, due to the fact that they experience a high level of chemical factors, and are able to secrete an enhanced quantity of matrix degrading enzymes (MDEs) [193, 379]. In particular, the production of proteolytic enzymes, such as matrix metalloproteinases (MMPs), is essential during the invasive phase: the dissolution of the ECM provides in fact both a space into which aggressive cells can move and a gradient which can be used by the cells themselves to direct their movement (i.e., haptotaxis); see [74, 286, 379]. The scattered individuals, evading destruction by the immune system, may subsequently enter the host bloodstream or lymphatics, extravasate at a distant site, and establish secondary colonies with devastating consequences for the wellbeing of the patient, as the likelihood of success of therapeutic interventions strongly decreases [162, 324].
