Chronic Inflammation and Pathogenesis of GI and Pancreatic Cancers

Abstract

Abstract:Keywords:The pathogenesis of cancer represents a complex and multifactorial process requiring a number of acquired and genetic defects. It is becoming increasingly apparent that many cancers originate from a chronic inflammatory process, The topic of this review is the inflammatory response and development of gastrointestinal (GI) and pancreatic cancers, Here, we describe the development of various gastric colorectal and pancreatic cancers through an inflammatory process. The tumor microenvironment which predisposes to tissue destruction, subsequent attempts at healing and accumulation of cellular damage with loss of cell cycle control mechanisms is discussed. Components of the tumor microenvironment that are important in the final common pathway leading to cancer include the tumor stroma, tumor-associated macrophages, cytokines and chemokines and reactive oxygen and nitrogen species. Common signaling pathways that link inflammation with cancer are described and include the COX-2, NF-KB and phosphatidyl inositol 3-kinase (PI3K) pathways. Finally, therapies that can be directed to the inflammatory process as either treatment or prevention of these cancers will be discussed including novel inhibitors of signaling pathways which are currently in development.

Increased Colorectal Epithelial Cell Proliferation and Crypt Fission Associated with Obesity and Roux-en-Y Gastric Bypass

“…Only 6 of 21 (28.6%) cases had neo-CK18 -positive cells evident in complete longitudinal crypts (mean crypt number, 9; range, 2-23). Eleven of 24 (45.8%) morbidly obese patients had crypts that contained neo-CK18 -positive cells (mean crypt number, 8; range, [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Neither the percentage of neo-CK18 -positive patients nor the overall number of apoptotic cells per crypt was significantly higher in morbidly obese patients compared with normal BMI individuals [P = 0.23 (m 2 test) and P = 0.16 (Mann-Whitney U test), respectively].…”

“…Obesity-related insulin resistance, leading to increased colonic insulin and insulin-like growth factor-1 exposure, increased adipokine levels, and elevated colonocyte oxidative stress and energy substrate availability have been proposed to explain this relationship (1,2). An alternative hypothesis stating that chronic inflammation links both obesity and colorectal carcinogenesis reconciles independent observations that obesity is a state of chronic systemic inflammation (11) and that chronic mucosal inflammation promotes colorectal carcinogenesis (12). Therefore, we also measured levels of serum markers of inflammation [C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor a (TNFa), and macrophage migration inhibitory factor (MIF)] and mucosal proinflammatory mediators [including mRNA levels of cytokines such as IL-1h, IL-6, TNFa, the cyclooxygenase (COX) enzymes, etc.]…”

No association between TNF-α-238 polymorphism and colorectal cancer in Iranian patients

“…Chronic inflammation and pro-inflammatory mediators including tumor necrosis factor alpha (TNF-a) may increase the risk of gastrointestinal (GI) cancer [1]. Recently, TNF-a-238 G/A gene promoter polymorphism was shown to be associated with immune-mediated disorders [2] and certain types of cancers, including gastric, uterine cervical, and colorectal (CRC) cancers [3].…”

“…An acquired JAK2 gene mutation (V617F) has been recently associated with myeloproliferative disorders [1]. The JAK2 V617F mutation, which causes the substitution of phenylalanine for valine at codon 617 in the JH2 domain, predicts to disrupt the autoinhibition of the JH1 catalytic domain by the JH2 domain.…”

The Association of Chronic Inflammation and Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

“…The persistence of chronic inflammation plays a critical role in initiating, sustaining and advancing tumor growth, and thus modulating the immune response may still be an alluring goal for therapeutic intervention. 22,23 Although a pathogenic role for chronic inflammation has been suggested in multiple tumor systems in tumor initiation, progression and metastatic potential, the mechanism of this www.intechopen.com important association is still not understood completely. The development of a tumor is associated with the growth and expansion of not only tumor cells but also stroma, vessels and infiltrating inflammatory cells, and it is the interaction between these different cell types that propagates tumor growth.…”