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Carcinogenesis Advance Access originally published online on May 2, 2008
Carcinogenesis 2008 29(5):890-894; doi:10.1093/carcin/bgn106
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The contribution of animal fat oxidation products to colon carcinogenesis, through modulation of TGF-β1 signaling

Fiorella Biasi, Cinzia Mascia and Giuseppe Poli*

Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy

* To whom correspondence should be addressed. Tel: +39 011 6705422; Fax: +39 011 6705424; Email: giuseppe.poli{at}unito.it


   Abstract
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 Abstract
Introduction
 Conclusions
 Funding
 References
 
It is now unanimously accepted that neoplastic cells tend to become less susceptible to the growth regulatory effects of transforming growth factor-β1 (TGF-β1), mainly because of reduced expression and/or activity of TGF-β1-specific receptors, as reported for many human cancers including colon cancer. Consequently, a sustained increase of TGF-β1 in the intestinal mucosa, like that caused by inflammatory processes and/or high dietary intake of animal fat, might become crucial for the progression of a neoplastic clone. In fact, this proapoptotic and prodifferentiating cytokine could eliminate neoplastic cells still susceptible to TGF-β1's antiproliferative action (TGF-β1 receptor-positive cells), indirectly favoring the expansion of TGF-β1 resistant ones (TGF-β1 receptors deficient or negative cells). The actual concentration of TGF-β1 in the colonic mucosa undergoing neoplastic transformation is still debated, and the phase of the relevant carcinogenetic process in which a reduced susceptibility to this antiproliferative molecule first occurs has not been precisely established yet. However, no doubt that TGF-β1 level and activity may be upregulated in cells of the macrophage lineage by animal fat oxidation products, such as oxysterols and aldehydes, as reviewed here. But phagocytes as well as fibroblasts constitutively express TGF-β1 and are accumulating in tumor-associated stroma. Thus, upregulation of this cytokine system within colonic tumor-associated stroma by excess dietary intake of cholesterol and n-6 polyunsaturated fatty acids appears as a primary mechanism of cancer progression at least in neoplastic lesions of the digestive tract.

Abbreviations: AA, arachidonic acid; HNE, 4-hydroxynonenal; IBD, inflammatory bowel disease; IL, interleukin; 5-LOX, 5-lipoxygenase; PUFA, polyunsaturated fatty acid; TGF-β1, transforming growth factor-β1


   Introduction
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 Abstract
 Introduction
Conclusions
 Funding
 References
 
Excess dietary intake of cholesterol and n-6 polyunsaturated fatty acids (PUFAs) with animal fats has been associated with an increased risk of developing colorectal cancer (1). Large amounts of lipid oxidation products become available, of both exogenous and endogenous origin, at the level of the colon mucosa. Certain cholesterol and n-6 PUFA oxidation products, e.g. oxysterols and hydroxyalkenals, besides exerting toxic and/or mutagenic effects also strongly stimulate expression and synthesis of transforming growth factor-β1 (TGF-β1) by cells of the human macrophage lineage (2,3).

This inflammatory and fibrogenic cytokine is fundamental to regulate intestinal epithelium cell growth because of its marked prodifferentiating and proapoptotic effects. However, once transformed, neoplastic cells tend to become less susceptible to the growth regulatory effects of TGF-β1, mainly because of reduced expression of TGF-β1 type I and/or type II receptors, as has been found for many human cancers including colon cancer (4–6).

An excessive increase of the steady-state concentration of TGF-β1 in the intestinal mucosa, like that caused by inflammatory processes and/or high dietary intake of animal fat, might become crucial for the progression of a neoplastic clone: this cytokine could stimulate differentiation and apoptosis in those neoplastic cell still susceptible to TGF-β1's antiproliferative action (TGF-β1 receptor-positive cells), while favoring the clonal expansion of TGF-β1 receptors deficient/negative neoplastic cells (Figure 1).


Figure 1
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  		Fig. 1. Elimination of TGF-β1 receptors-positive cells by the fat oxidation-induced proapoptotic cytokine, and consequent clonal expansion of TGF-β1 receptors deficient and negative neoplastic cells in colonic mucosa.

 
Major animal fat oxidation products, including oxysterols and 4-hydroxyalkenals, may favor the clonal expansion of TGF-β1 receptor-deficient/negative colon epithelial cells by upregulating expression of TGF-β1 and of related transduction molecules in the macrophages and fibroblasts, which surround the neoplastic lesion. The result is a sustained presence of relatively higher concentrations of TGF-β1 and other growth-modulating factors in the area of the neoplastic proliferation.

We thus deemed it of interest to analyze and review all the recent literature available on the effects of different animal fat oxidation products on TGF-β family members and on the related molecular signaling, with the focus on cancer progression.

Animal fat oxidation products
Because of extensive changes to lifestyles over the last 50–60 years, Western diet has undergone significant modifications, now including a marked increase in fat intake. In particular, dietary lipids, especially PUFAs and cholesterol/cholesterol esters, have increased and varied in type. These dietary changes are associated with an increase in chronic inflammatory, autoimmune and vascular diseases, as well as cancer development (1,7–10).

Northern America and Western Europe people consume diets containing large amounts of red and processed meat compared with Eastern European and in Mediterranean countries, where diets contain more fruit, vegetables, fish and olive oil. Several epidemiological and pathological studies have provided evidence that the ‘Westernization’ of dietary and nutritional practices is an important determinant in inflammatory bowel diseases (IBDs), colorectal polyps and colorectal cancer.

Numerous studies have underlined the role played by an unbalanced, excessive intake of animal-derived omega-6 fatty acids, namely linoleic acid and arachidonic acid (AA) in the pathogenesis of these chronic diseases (1,10–13). It has been clearly documented that, among cell membrane phospholipids, linoleic acid and AA are substrates for the synthesis of a range of biologically active mediators, including prostaglandins, thromboxanes and leukotriene, which convey inflammatory responses by modulating interleukin (IL)-6, IL-1β, tumor necrosis factor-{alpha}, TGF-β1 and interferon-{gamma} expression (14–17). Furthermore, lipids represent one of the most important cell targets of oxidative stress: AA is a selective substrate for the non-enzymatic oxidative break down of lipid cell membranes, known as lipid peroxidation, which leads to the formation of a variety of molecules with toxic and mutagenic effects (18,19). Lipid peroxidation can be initiated by different free radicals and is characterized by a rise of both reactive oxygen species and radical intermediates, which often reduce the cell's antioxidant defenses and cause an imbalance between oxidative and reductive reactions. This process is commonly known as oxidative stress, and may be due to different causes: unbalanced diet with reduced antioxidant intake or increased omega-6 PUFA intake, intestinal infections, which recruit activated phagocytes, environmental and genetic factors, including chronic inflammation of the gut.

Enhanced oxidative degradation of membrane lipids involves the cleavage of lipid hydroperoxides and leads to the formation of reactive aldehydes; that most considered to date is 4-hydroxynonenal (HNE). HNE derives from oxidative degradation of omega-6 fatty acids and, due to the presence in its molecule of a hydroxyl group close to the double bond, it readily reacts with thiol- and amino-groups, thus causing DNA damage (with oxidation of guanine to form 8-oxo-7,8-dihydro-2'-deoxyguanosine), changes in the structure of membrane phospholipids and proteins, and enzymatic inactivation. An increasing bulk of experimental evidence points to HNE as a candidate molecule for a role in the pathogenesis of numerous inflammatory and degenerative processes, including gastrointestinal diseases and cancer (20,21).

Another class of reactive carbonyls may originate from the oxidation of n-6 PUFAs esterified to cholesterol; these are thus termed ‘core aldehydes’. The two main compounds of this class are 9-oxononanoylcholesterol and 5-oxovaleroylcholesterol, i.e. the oxidation products of cholesteryl linoleate and cholesteryl arachidonate, respectively (22). Oxidized cholesterol PUFA esters may become harmful constituents of food of mammalian origin, after its heating or prolonged storage (23). Of interest, 9-oxononanoylcholesterol was shown capable of inducing an inflammatory phenotype in endothelial cells, conferring on them the ability to actively bind monocytes (24).

Besides PUFA oxidation products, oxysterols, i.e. a family of 27-carbon cholesterol derivatives, appear to be another important class of lipid oxidation products capable of influencing the expression and evolution of human disease processes, including cancer. It is now accepted that these compounds modulate various signaling pathways, thus exerting a number of biochemical effects, which include the promotion of chronic inflammation, fibrosis and programmed cell death (for review see refs 8,25,26). Oxysterols may be absorbed with the diet or can be originated endogenously. Food products high in cholesterol, such as powdered milk, cheese, meats and eggs, are susceptible of forming cholesterol degradation and oxidation products after prolonged storage or cooking (27,28). Exogenous oxysterols are completely absorbed from the bowel, cleared from the plasma and are taken up by different tissues and organs more rapidly than parental non-oxidized cholesterol (8,29). Endogenous production of oxysterols may partly occur within the tissues, through a non-enzymatic oxidation of cholesterol, which involves oxygen species reactions, or occurs via enzymatic catalysis; the latter route is, for some oxysterols, the only way of formation (25).

Oxidized dietary lipids, colon inflammation and TGF-β1 signaling
The colon mucosa provides a physiological barrier against potentially pathogenic components of the diet, as well as against intestinal flora present in the lumen. Colon epithelial cells counteract potential insults through a highly complex network of cell signals that control the intestinal immune response, inflammatory status and mucosal wound healing. However, continuous exposure of the intestinal mucosa to inflammatory agents, such as bacterial cell products, inflammatory cytokines or those related to genetic disorders, may derange the proper intestinal cell function. Increased free-radical production, generally resulting from reactive oxygen and nitrogen intermediates generated by infiltrating phagocytic cells, high dietary lipid intake or reduced antioxidant defenses, might maintain an active inflammatory status, which sustains intestinal damage and predisposes to colon cancer (10,30–32). A large body of epidemiological evidence points to lipid oxidation products and intestinal microflora as the main agents responsible for oxidative redox imbalance that is sufficiently accentuated to induce cell and tissue damage and consequently to contribute to sustaining IBDs such as ulcerative colitis or Crohn's disease (33,34).

Considerable literature supports a significant role for n-6 and n-3 PUFAs in modulating inflammatory processes, but the underlying molecular mechanisms are still unclear. It is known that oxidation of animal fat via the cyclooxygenase and 5-lipoxygenase (5-LOX) enzymatic pathways generates key inflammatory molecules, like prostaglandin E2 and leukotriene B4. The action of prostaglandin E2 and leukotriene B4 on polymorphonuclear cells and macrophages enhances the production of inflammatory cytokines like tumor necrosis factor-{alpha}, IL-1 and IL-6. On the contrary, eicosapentaenoic acid and docosahexaenoic acid, contained in fish-derived foods in large amounts, are known to inhibit the enzymatic metabolism of n-6 PUFA and to induce production of alternative eicosanoids of the leukotriene B5 and prostaglandin E3 series, which exert an inflammatory effect 10–100 times lower (for a review see refs 17,35). More recently, eicosapentaenoic acid and docosahexaenoic acid have been shown to generate, through involvement of cyclooxygenase-2, very strong antiinflammatory mediators, known as resolvins and protectins (36).

Among inflammatory cytokines produced by cells of the macrophage lineage following activation with oxy-derivatives of dietary animal fat, TGF-β1 might play a special role in the link existing between inflammation and carcinogenesis. TGF-β1 is normally mostly expressed in mesenchymal cells and is involved in the regulation of cell processes like proliferation, survival, differentiation and apoptosis. This cytokine is crucial in tissue remodeling during wound repair; it promotes deposition of extracellular matrix proteins and proliferation of fibroblasts and smooth muscle-like cells (myofibroblasts), as well as inhibiting the growth of normal epithelial cells (37). TGF-β1 acts on epithelial cell proliferation by blocking the cell cycle in the G1 phase and activating transduction of signals of differentiation and apoptosis (38–40). In normal colon epithelium, TGF-β1 permits differentiation of stem cells, which continually migrate from bottom to top of the crypts, differentiate into enterocytes and finally undergo apoptosis and are shed into the lumen (41). Direct proapoptotic effect implies the co-operation of TGF-β1 with the death receptor apoptotic pathway (Fas), c-jun N-terminal kinase and p38 mitogen-activated protein kinase and the mitochondrial apoptotic pathway (39). Of interest, this cytokine has also been reported to mediate the removal of transformed (precancerous) cells through a reactive oxygen species-mediated ‘intercellular’ induction of programmed cell death, in which the interaction of non-transformed and transformed cells leads to selective elimination of the latter ones (42–44).

Because of this key role in regulating colonic cell numbers and function, any significant change in TGF-β1 steady-state levels and signaling might be expected to promote dysplastic or even neoplastic events.

A direct correlation between n-6 PUFA degradation products, such as HNE and malonaldehyde, and TGF-β1 overproduction in fibrotic diseases, i.e. liver fibrosis, atherosclerosis and Crohn's disease, has been demonstrated (4,45–48). Pathophysiological amounts of HNE induced TGF-β1 expression and synthesis in promonocytic and macrophagic cells (2) and increased both expression and synthesis of procollagen type I in primary cultures of human stellate cells (49). The HNE-dependent modulation of these genes most probably implies the activation of kinases leading to the upregulation of the redox-sensitive transcription factor activator protein-1 (50). More recently, the search for potential cross talk between HNE and TGF-β1 signals has indicated HNE directly influences the activation of small mothers against decapentaplegic (Smad) proteins, i.e. the main transduction proteins involved in TGF-β1-mediated cell signaling (51).

The importance of aldehyde products of PUFA degradation in colon diseases has been pointed up in epidemiological studies on fatty acid profiles in IBD patients, showing a net decrease of n-3 fatty acids in Crohn's disease (52–54). Increasing dietary intake of n-3 PUFA has been employed to reduce high levels of inflammatory AA metabolites and lipid peroxidation products. Notwithstanding various attempts, there are not yet sufficient data to demonstrate clearly that treatment with n-3 PUFA supplementation can induce total disease remission (for a review see ref. 54).

As regards cholesterol and cholesterol ester oxidation products, upregulation of the expression and synthesis of TGF-β1 has been demonstrated in human promonocytic cells and murine macrophages, challenged, respectively, with oxysterols (3) and 9-oxononanoylcholesterol (55), in concentrations detectable in human disease processes.

Recent work on the modulation of TGF-β1 levels and activity by lipid oxidation products has mainly been restricted to oxy-compounds generated by non-enzymatic mechanisms, probably because experimental research has mainly targeted the role of lipid peroxidation, i.e. non-enzymatic oxidative break down of membrane PUFAs, in the pathogenesis of metabolic and degenerative diseases. Very recently, reliable data supporting the upregulation of TGF-β1 mediated by products of enzymatic oxidation of AA have become available: treatment of rat vascular smooth muscle cells with a cytochrome P450 AA metabolite, namely 20-hydroxyeicosatetraenoic acid, was found to induce TGF-β1 and hence to reduce cell proliferation (56). Prostaglandin E2, whose synthesis by leptomeningeal cells is stimulated by lipopolysaccharide, was shown to regulate production of TGF-β1 by glial cells and cortical neurons (57). Other work clearly shows that the 5-LOX pathway plays a contributing role in chronic inflammation and TGF-β1-dependent tissue remodeling. Evaluation of IL-13 effects in 5-LOX knockout mice, versus the corresponding wild-type mice, shows that this cytokine can exert its proinflammatory effect only through involvement of LOX, namely by increasing levels of 5-LOX-activating protein (58). Further, class 4 leukotrienes appear to markedly upregulate both TGF-β1 messenger RNA and protein expression in airway epithelial cells (59).

Impairment of TGF-β1 activity and colon cancer
Patients with IBD are at increased risk of developing colorectal cancer (32,60,61). In the chronically inflamed intestine, persistent overproduction of lipid peroxidation end products, such as aldehydes and epoxides, may be tumorigenic due to their ability to produce chemical adducts to DNA, oxidize DNA bases or cause errors in DNA repair. These DNA changes may lead to mutations in genes critically involved in the regulation of colon cell proliferation, survival and migration (62–64).

Because of the crucial role of TGF-β1 signaling in the negative regulation of cell proliferation (65,66), somatic mutations and loss of expression of genes involved in this specific pathway may indeed induce major changes in cell growth control mechanisms and favor tumor progression (67,68).

At present, a high percentage of human colorectal cancers show mutations in genes coding for specific components of the TGF-β1 pathway. Alterations of type I and, particularly, type II TGF-β1 receptors occur frequently in human colon adenocarcinoma in the intestinal epithelial cells (5, 69), although they are not consistently related to the degree of tumor dedifferentiation (4). Further, mutations in the Smad4 gene, which encodes for a key mediator of TGF-β1-dependent cell growth inhibition, have been observed in the colonic mucosa of about half of the people with familial juvenile polyposis, an autosomic dominant condition that strongly predisposes to gastrointestinal cancer (70). Reliable evidence has been obtained in a transgenic mouse model that Smad4 acts as a crucial suppressor gene within the gastrointestinal environment (71). Other mutational changes in the Smad pathway have been described, e.g. involving Smad2, an essential component of the Smad2/3/4 active transcriptional complex, but only in a minority of colon cancers (72).

In addition to changes in TGF-β1 signaling, a net decrease in its expression and synthesis also occurs in colon adenocarcinoma (4,46). This reduced concentration of the cytokine has been related to a general lower availability of peroxidative substrates, in the form of AA and linoleic acid, in tumor membranes (73), which for instance does not afford sufficient production of HNE, a recognized inducer of TGF-β1 (2). The simultaneous reduced susceptibility to lipid oxidation and low tumor tissue content of TGF-β1 might further weaken growth control mechanisms because under these conditions the demonstrated synergistic interplay between mitogen-activated protein kinase and Smad signaling pathways, which induces cell apoptosis, would not occur to a sufficient extent (51). Very recently, Bacman et al. (74) found low levels of TGF-β1 in about two-third of 310 colon carcinomas, the cytokine being relatively more expressed in low-grade carcinomas.

TGF-β1 signaling by cells of stroma-associated tumors may selectively favor proliferation of TGF-β1-insensitive neoplastic cells
In human colon cancer, contrary to the net reduction of its content observed in the colonic epithelium, TGF-β1 has been found to increase in the tumor stroma versus the surrounding, apparently normal, tissue. This is mainly due to the presence of numerous inflammatory cells around and within the tumor mass. Consequently, since these cells also strongly express TGF-β1 receptors, the entire TGF-β1 system might become more represented in the stroma than in the epithelium of colon adenocarcinoma. Indeed, a crucial role was recently recognized to the stromal component of tumors in their overall growth and progression. Besides the obvious role of inflammatory cells in cancer promotion, fibroblasts of the stroma are now considered to modulate cancer growth by secreting inflammatory, fibrogenic, apoptotic cytokines (75,76).

Fat oxidation products appear in principle able to stimulate production of TGF-β1, not only in phagocytes but also in fibroblasts. In addition, the inflammation-associated increase of reactive oxygen species steady-state levels will guarantee prompt activation of the latent cytokine pool (77). Thus, as depicted in Figure 2, an increased availability of oxidized lipids, with consequent upregulation of TGF-β1 within the stroma of a colonic neoplasia, may be thought to contribute significantly to a selective and more efficient elimination of those neoplastic cells still susceptible to the proapoptotic effect of the cytokine, indirectly permitting the proliferative expansion of TGF-β1-insensitive neoplastic cells (78). The elimination mechanism strongly resembles that early described by Bauer's group as ‘intercellular induction by apoptosis’ referred to transformed, yet precancerous cells (42,43).


Figure 2
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  		Fig. 2. Animal fat oxidation products appear in principle able to stimulate production of TGF-β1 by phagocytes and fibroblasts of colon cancer-associated stroma.

 

   Conclusions
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 Introduction
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Funding
 References
 
The important role of lipids as mediators in a wide range of cellular responses, including cell growth, differentiation and apoptosis, and the close connection with the abnormal biological activities of TGF-β1 observed in different intestinal diseases underlie the hypothesis of the involvement of dietary lipids in modulation of TGF-β1 cell signaling.

Increased levels of animal fat oxidation products, such as oxysterols and aldehydes, are indeed associated with inflammatory conditions that may affect colon mucosa. Sustained increase of TGF-β1 levels as induced by oxidized dietary lipids in inflammatory and stromal cells that surround/infiltrate the epithelial tumor mass very probably strengthens growth inhibitory signals, which will be properly elaborated by normal colon epithelium cells, precancerous cells and neoplastic cells still sensitive to the cytokine's inhibitory effect, but on the contrary taken by highly transformed cells (TGF-β1 insensitive) as a favorable escape mechanism for independent proliferation and advanced carcinogenesis. Certainly, such an escape mechanism would be favored by the marked proangiogenetic and immunosuppressive effects (40) that an increased cytokine's level in tumor's stroma may exert. Last but not least, the high profibrogenic and proinflammatory effect of TGF-β1 may feed all these tumor-promoting events by increasing both number and activation of phagocytes and fibroblasts in the colon cancer microenvironment.


   Funding
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 Abstract
 Introduction
 Conclusions
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References
 
Italian Ministry of University, Rome; Region of Piedmont (Ricerca Sanitaria Finalizzata 2006 and 2007 to G.P., 2006 to F.B.); University of Turin, Italy.


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
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Received March 17, 2008; revised April 15, 2008; accepted April 20, 2008.


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