**5.1 Mechanism**

*Multidisciplinary Approach for Colorectal Cancer*

**4.1 Mechanism**

of the diet associated with the development of obesity [4].

already committed to metabolic reprogramming [45].

IGF-1 has been established as a risk factor for CRC [45].

further underscores the importance of combined integrated effects of nutrients/ foods over their individual effects. These effects probably do not only reflect the imbalance between energy intake and expenditure but the often suboptimal quality

Overnutrition increases the supply of glucose and fat that can feed into metabolic reprogramming to fuel cancer cell proliferation. In addition, glycolysis has been shown to be enhanced in cancer cells of obese individuals. As obesity is often associated with metabolic syndrome (MS) and diabetes, characterized by hyperglycemia and/or hypertriglyceridemia, an abundance of circulating nutrients are available for tumor development, even between feeding periods [45]. Autophagy, the process whereby cancer cells digest and recycle their cellular contents during periods of low nutrient availability, can provide cancer cells with lipids, amino acids, and nucleotides required for proliferation [46]. Obesity has been shown to induce autophagy, particularly in adipocytes [45]. These obesity-associated metabolic adaptations facilitate the development of cancer traits that include insensitivity to anti-growth signals, resistance to cell death, and deregulation of cellular energetics [47]. Hence, interactions between cancer cell energetics and systemic metabolism highlight unique therapeutic strategies and interventions, particularly among obese individuals, as cancer cells may be more sensitive to metabolic interference, having

In addition, obesity and MS are associated with abnormalities in insulin signal-

Higher body fatness is associated with increased insulin levels, which can promote cell growth and inhibit apoptosis and has been linked to a greater risk of CRC in humans

Physical activity (PA) includes all movements performed in daily life, including sport, whether recreational or competitive [30], as well as that performed in occupational, transport, recreational, and household settings [7]. In epidemiological studies, PA is computed by combining intensity, duration, and frequency of different types of PA, with subjects being classified into three levels of PA, namely, low, moderate, or high. PA is usually divided into four types of activity related to occupational, transport, recreational, and household settings. Total PA is calculated as the sum of the four types or any of the four types that are presented as all-type PA. Thus a major barrier to conducting meta-analyses is the disparity between the

[50, 51] and in experimental studies [52]. Body fatness also stimulates the body's inflammatory response, which can promote CRC development [53, 54]. Overall, there are convincing mechanistic data supporting a link between body fatness and CRC [8].

ing, growth factor signaling, and glucose metabolism [48]. One growth factor implicated in cancer risk and progression is insulin-like growth factor (IGF)-1. Hyperglycemia and hyperinsulinemia, diagnostic criteria of MS, increase IGF-1 production and bioavailability. Furthermore, hyperglycemia suppresses IGF-1 binding protein synthesis, while hyperinsulinemia promotes expression of growth hormone receptor and subsequent IGF-1 synthesis [48]. Growth and survival functions of IGF-1 give it the potential to have an impact on many characteristics of cancer, including sustained proliferative signaling, insensitivity to anti-growth signals, induction of angiogenesis, and metastatic potential [49]. As a result, elevated

**16**

**5. Physical activity**

measures of PA [7].

PA reduces body fatness and therefore has a beneficial effect on CRC risk, possibly due to a reduction in insulin resistance and inflammation [50, 53, 54]. However, it is unclear whether PA that is not accompanied by weight loss has a significant impact on these pathways. Other mechanisms through which PA may lower CRC risk include the stimulation of digestion and reduction of gastrointestinal (GI) transit time, although robust data to support this mechanism in humans is limited [58]. Overall, mechanistic data to support a link between PA and CRC are moderate in strength [8].
