Increased expression of fatty acid synthase in human aberrant crypt foci: Possible target for colorectal cancer prevention

Abstract

Aberrant crypt foci (ACF), the earliest identified monoclonal lesions in the colon, provide insights into changes that promote and/or accompany the transformation of normal colonic epithelial cells to colorectal cancer. Fatty acid synthase (FAS), the primary enzyme involved in de novo lipogenesis from carbohydrates, is expressed at low levels in most normal human tissues but is elevated in several human neoplasms including colorectal adenomas and carcinomas. To determine if this pathway is altered even earlier in colorectal tumorigenesis, 35 human ACF from 21 patients were evaluated for the immunohistochemical expression of FAS. Sections of colon cancer served as positive controls, and normal colonic mucosa distant from cancer or ACF served as negative controls. FAS expression was increased in 30 (86%) ACF compared with that in adjacent normal colonic mucosa. The expression of FAS in ACF was not related to the degree of dysplasia or to the number of crypts in the ACF. The over expression of FAS in a high proportion of ACF suggests that this enzyme plays an important role very early in colorectal tumorigenesis and may be a target for chemoprevention. ' UICCKey words: human aberrant crypt foci; colon cancer precursors; biomarkers; chemoprevention; colorectal cancer Fatty acid synthase (FAS) is the only mammalian enzyme capable of de novo long-chain fatty acid synthesis from smaller carbohydrate substrates. 1 In adults, it is expressed primarily in hormone-sensitive tissues and those with high lipid metabolism. 2 The expression and activity of FAS in normal tissues is highly regulated by diet, hormones and growth factors: carbohydrates, insulin, and transforming growth factor-beta all upregulate the expression and activity of FAS (reviewed in Ref. 3). In humans on a normal diet in industrialized countries, the expression and activity of FAS is low, even in lipogenic organs like liver and adipose tissue, because of its suppression by small amounts of dietary fatty acids. 3,4 Consequently, FAS plays only a minor role in human lipogenesis. 4 In contrast, FAS is highly expressed by many human cancers including prostate, breast, ovarian, endometrial, thyroid, colorectal (reviewed in Ref. 5); bladder, 6 lung, 7 oral mucosa, 8 tongue, 9 esophageal, 10 and stomach 11 carcinomas as well as melanoma, 12 retinoblastoma, 13 and nephroblastoma. 14 Increased expression of FAS has also been reported in some benign or preinvasive lesions of the prostate, colon, breast (reviewed in Refs. 5,15); lung, 7 cutaneous nevi, 12 and stomach. 11 We evaluated the expression of FAS in aberrant crypt foci (ACF), the earliest microscopically identified monoclonal lesions in the colon. 16 Increased expression of FAS was seen in 30 of 35 (86%) of ACF from 21 patients with sporadic colorectal cancer or familial adenomatous polyposis (FAP). Material and methodsParaffin-embedded sections of ACF with adjacent normal colonic mucosa or samples of human colorectal cancers were stored at 4°C for several months prior to immunohistochemical analysis as d...

Dietary n-3/long-chain n-3 polyunsaturated fatty acids for prevention of sporadic colorectal tumors: A randomized controlled trial in polypectomized participants

“…Major genetic polymorphisms/single nucleotide polymorphisms (SNPs) especially related to research on FAs and the development of CRTs may include enzymes for FA synthase (FAS) and FA desaturase (FADS1, FADS2), pro-/anti-inflammatory responses (Interleukins, tumor necrosis factor [TNF]-alpha, peroxisome proliferator-activated receptor [PPAR]-gamma, epidermal growth factor receptor [EGFR], caudal-type homeobox protein 2 (CDX2), and prostaglandin E [PGE]) in addition to those associated with folate metabolism (methylene tetrahydrofolate reductase [MTHFR]) and vitamin D receptor (Bsml, Fok1), alcohol and acetaldehyde metabolism (ADH1B and ALDH2), and xenobiotic/ drug/carcinogen phase I and phase II metabolism (cytochrome P450 (CYP) and glutathione family), such as CYP1A1 associated with tobacco smoking, and NAT1 (N-acetyltranferase 1) and NAT2 related to decomposed amino acids by pyrolysis etc [30,[60][61][62][63][64]. Future studies warrant recruitment of a number of study subjects sufficient to conduct genetic analyses or nutrigenetics to elucidate gene-gene and gene-diet interactions, locate high-or low-risk populations, and optimize benefits and minimize risks in relation to a given diet.…”

Colonic Mucosal Fatty Acid Synthase as an Early Biomarker for Colorectal Neoplasia: Modulation by Obesity and Gender

“…[13, 33, 34]. While this is the first report (to our knowledge) to demonstrate overexpression of FASN in the uninvolved mucosa, its expression has been reported to be elevated in aberrant crypt foci [35, 36], adenomas [37] and carcinomas [25]. The biological consequences of FASN include increased endothelial activity (important given that increased micro-circulation is one of the earliest events in colorectal carcinogenesis) as well as proliferation [38].…”

Tumor cell metabolism

“…[78][79][80][81][82][83][84][85][86][87] This overexpression has been shown to participate in very early tumorigenesis, tumor growth and survival. 76,86 FASN upregulation also protects cells from death by inhibiting the intrinsic pathway of apoptosis. 80 The siRNA-mediated silencing of FASN or the use of FASN inhibitors, such as cerulenin, C75 and orlistat, has been shown to induce apoptosis in several cancer lines.…”