Pathogenesis of Colorectal Cancer
Despite the new technological advancements in early diagnosis and therapeutic strategies, the clinical outcome of patients with colorectal malignancies has changed relatively little over the past 50 years [1,2]. This concept clearly underlines the need fo
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Introduction Despite the new technological advancements in early diagnosis and therapeutic strategies, the clinical outcome of patients with colorectal malignancies has changed relatively little over the past 50 years [1,2]. This concept clearly underlines the need for new therapeutic approaches based on a greater understanding of the molecular basis of these tumors. During the last 2 - 3 decades of the past century, several exciting advances have been made regarding factors predisposing to colorectal cancer. For instance, it has been shown that a definite fraction of these tumors is truly hereditary and, thus, transmitted from one generation to the next in accordance with an autosomal dominant model [3, 4]. Similarly, several environmental factors - mostly related to diet and lifestyle - have been identified which seem to playa certain role in colorectal cancer development [5]. Moreover, there is evidence that adenomatous polyps represent the natural precursor of intestinal malignancies, and that their systematic removal may prevent cancer occurrence [6]. Traditionally, colorectal cancer development has been viewed as an ordered process in which three main phases could be discerned: initiation, promotion and progression [7]. The recent explosion of molecular biology provided definite proof that stable alterations in the structure or sequence of DNA (mutations) represent the initiating event in tumorigenesis; these are followed by an uncontrolled expansion of the neoplastic clones which characterizes tumoral growth [8]. Several classes of genes have been identified (oncogenes, tumor suppressor genes, mutator genes) the alterations of which seem to be crucially important both in the initiation and in the promotion/progression of human tumors [9,10]. Thus, it is now clear that cancer results from a series of genetic alterations leading to the progressive and irreversible loss of normal control of cell growth and differentiation. These concepts apply virtually to all malignancies but are particularly evident in colorectal carcinoma, where the ordered sequence "normal mucosa - small adenoma - large adenoma - cancer" may allow the characterization of genetic changes in each phase of tumor progression [11]. It is therefore possible to explore in great detail the complex interaction between various environmental factors and the molecular events leading to colorectal neoplasia. In chapter 1 I focused on the main aetiological factors implicated in colorectal cancer development. In this chapter - after a brief introduction on the main M. Ponz de Leon, Colorectal Cancer © Springer-Verlag Berlin Heidelberg 2002
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Pathogenesis of Colorectal Cancer
causes of intestinal tumors - I aim to analyze the main pathogenetic pathways leading to colorectal neoplasms under different clinical conditions. The main message is that the same apparent phenotypic manifestations (cancer) may result from different molecular alterations and, presumably, from different "environment-gene interactions". These new concepts might be of relevance for
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