Abstract
Simple SummaryColorectal cancer is the third most deadly and fourth most commonly diagnosed cancer in the world. Beside incorrect lifestyles, such as smoking or excessive consumption of red meat and alcohol, inflammatory bowel diseases are considered driving factors for colorectal cancer onset and development. It is known that chronic inflammatory processes can lead to both intestinal barrier disruption and perturbation of microbial flora, thus increasing cancer risk. To date, no treatment against these inflammatory pathologies has proved efficient and resolutive. The glycoprotein lactoferrin, a safe supplement for infant and adult foods, is involved in immune defense and endowed with a number of properties, including anti-microbial, anti-inflammatory and anti-cancer activities. This review outlines the most recent studies on lactoferrin as a potential candidate in the prevention and treatment of intestinal inflammatory pathologies that are associated with increased risk of colorectal cancer.The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.
Highlights
Lactoferrin (Lf) was first fractionated as an unknown “red fraction” from cow’s milk in1939 [1]
inflammatory bowel diseases (IBDs) patients generally show an immune over-responsiveness to commensal bacterial antigens, resulting in the activation of many pro-inflammatory cytokines, such as IL-1β, tumor necrosis factor (TNF)-α, IL-6 and IL-12, related to the increase of neutrophil and pro-inflammatory macrophages [146,232]. It is observed the loss of some tight junction (TJ) molecules, including claudins, occludin, and zonula occludens, which are involved in the maintenance of intestinal epithelial barrier, increasing the host susceptibility to infections, inflammatory disorders and cancer [233,234]
Inflammatory bowel disease is a multifactorial pathology, primarily linked to an aberrant immune response to gut commensal flora, mainly bacteria, in a genetically susceptible host. Disruption of this normal microbial-host communication network has deleterious consequences for the host and it is associated to higher risk for colorectal cancer
Summary
Lactoferrin (Lf) was first fractionated as an unknown “red fraction” from cow’s milk in. Two major peptides, derived from the Lf N-terminal tryptic digestion, have been described, Lactoferricin (Lfcin) and Lactoferrampin (Lfampin) These positively charged peptides, physiologically involved in gut homeostasis, are endowed with numerous biological functions, including anti-microbial and anti-cancer ones [24,25]. Adult oral consumption of recombinant hLf from transgenic cow milk results in its complete digestion in the upper gastrointestinal tract [46], while only 40% of bLf is degraded [47] It appears that, in human adults, bLf is more resistant to proteolysis than hLf, suggesting that hLf is “designed” to be ingested orally only during infancy. The optimization and the efficacy of bLf supplemented products are still under debate as bLf bioavailability strictly depends on the source and the methods for industrial production, which can influence its purity, integrity, stability and, its activity [21]
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