Do Pathophysiologic Mechanisms Linking Unhealthy Lifestyle to Cardiovascular Disease and Cancer Imply Shared Preventive Measures?　― A Critical Narrative Review ―

Abstract

Growing evidence has shown a bidirectional link between the cardiologic and oncologic fields. Several investigations support the role of unhealthy behaviors as pathogenic factors of both cardiovascular disease and cancer. We report epidemiological and research findings on the pathophysiological mechanisms linking unhealthy lifestyle to cardiovascular disease and cancer. For each unhealthy behavior, we also discuss the role of preventive measures able to affect both cardiovascular disease and cancer occurrence and progression.

Although scientific research and international healthcare policies have focused on cardiovascular disease (CVD) and cancer for several decades, these conditions remain leading causes of morbidity and mortality, accounting for 17.5 million and 8.2 million deaths per year, respectively, according to a World Health Organization report.¹ Epidemiological studies have shown that classical modifiable cardiovascular risk factors are also associated with malignancy. A recent observational study has reported a significant association between the presence of traditional CVD risk factors and 10-year atherosclerotic CVD risk score and cancer.² A graded association between 7 lifestyle factors (smoking, physical activity, obesity, dietary intake, total cholesterol, blood pressure, and blood sugar), as included by the American Heart Association in the ideal cardiovascular health definition,³ and CVD/cancer incidence has been observed.^4,5 Experimental and clinical research has shown that common pathogenic mechanisms may explain, at least in part, the association between cardiovascular modifiable risk factors and cancer. In this review, for each unhealthy behavior known as a cardiovascular risk factor, including physical inactivity, poor dietary pattern, alcohol abuse, and smoking, we report epidemiological data showing a correlation between the unhealthy behavior and cancer. We also discuss the main biological pathways that may contribute to both CVD and cancer risk (Figure 1). Furthermore, we summarize the main strategies aimed at modifying unhealthy behaviors that are able to reduce cancer development and progression. Indeed, adopting simple healthy behaviors has been found to affect both CVD and cancer risk.⁶

Figure 1.

Schematic of hared pathophysiologic mechanisms linking unhealthy behaviors to cardiovascular disease and cancer, and main preventive measures. IGF, insulin-like growth factor; VSMC, vascular smooth muscle cells.

Reported evidence highlights several pathways, including inflammation, oxidative stress, and neo-angiogenesis, that are involved in the pathogenesis and progression of both CVD and cancer.^7–9 These shared pathways form the basis of a paradigm shift in cardio-oncology and pave the way to reverse cardio-oncology,¹⁰ a new field that focuses on the inherent risk of cancer development and progression in CVD patients.

Literature Search

This narrative review was based on recent reviews^7–11 that highlight the presence of an inherent cancer risk in patients with classical cardiovascular risk factors linked to lifestyle, including physical activity,^7,8,11 diet,^7,10 alcohol,⁹ smoking,^7,9,10 and obesity.^7,9,10 In order to further assess the cancer risk associated with these unhealthy behaviors, we performed a literature search in the PubMed database using the following terms: “cancer” AND “physical activity” OR “diet” OR “alcohol” OR “smoking” OR “obesity”. Selection criteria included articles that were meta-analyses, prospective observational studies, or case-control studies; articles published during the past 10 years; and studies that evaluated the incident risk of cancer associated with each risk factor. References of retrieved records were also manually searched to identify other relevant publications. Studies with inconclusive findings and articles for which the full text was not in English were excluded.

Physical Inactivity

It is well known that physical activity reduces the main cardiovascular risk factors and the risk of adverse cardiovascular events. Growing data also show an association between sedentary behavior and cancer risk. A pooled analysis including 1.44 million participants, which to our knowledge is the largest study on physical activity and cancer risk, found higher levels of leisure-time physical activity to be associated with a reduction in incident risk of several cancers as compared with lower levels of physical activity.¹² Cancer risk reduction was ≥20% for 7 types of cancer, including esophageal adenocarcinoma, liver, lung, kidney, gastric cardia, and endometrial cancers, and myeloid leukemia.¹² A dose-dependent benefit seems to be present between physical activity and both cancer and cardiovascular mortality risk.¹³ Although increasing the level of physical activity has been found to be associated with greater benefit in terms of reduced CVD and cancer risk (Table 1), the further advantage conferred by the highest levels of physical activity compared with moderate activity is minimal.¹⁴ The association between reduced CVD risk and higher levels of physical activity has also been observed in cancer patients.¹⁵ In women with nonmetastatic breast cancer, exercise has been found to be associated with a graded decrease in cardiovascular events, with a 35% risk reduction for women engaged in the highest levels of exercise.¹⁵

Table 1. Dose-Response Relationship Between Physical Activity Level and Risk of Breast Cancer, Colon Cancer, and Cardiovascular Disease

	MET min/week
	<600	600–3,999		4,000–7,999		>8,000
		RR	95% UI	RR	95% UI	RR	95% UI
Cancer site
Breast	Ref.	0.97	0.94–1	0.94	0.90–0.98	0.86	0.83–0.90
Colon	Ref.	0.90	0.85–0.95	0.83	0.77–0.90	0.79	0.74–0.85
CVD
Ischemic heart disease	Ref.	0.84	0.79–0.89	0.77	0.70–0.84	0.75	0.70–0.81
Stroke	Ref.	0.84	0.78–0.92	0.81	0.69–0.94	0.74	0.66–0.81

Data from a Bayesian meta-analysis (Kyu et al¹⁴) including prospective cohort studies assessing the associations between the dose of physical activity standardized (MET min/week) and cancer and CVD risk. CVD, cardiovascular disease; MET, metabolic equivalent; RR, pooled risk ratio; UI, uncertainty interval.

Several biological mechanisms activated by physical activity mediate its favorable effects on the cardiovascular system and cancer prevention (Table 2 summarizes the molecular mechanisms that affect both cancer pathogenesis and atherosclerosis).^9,16–28 Of note, acute and intense exercise is associated with the production of potentially harmful biological mediators, including reactive oxidative species (ROS)¹⁶ and interleukin (IL)-6.²⁷ However, over time, regular exercise induces adaptive processes, such as the increased synthesis of antioxidant enzymes. Furthermore, the acute increase in IL-6 that occurs during exercise is not associated with an increase in classical pro-inflammatory cytokines.²⁷ Instead, IL-6 in this setting induces an increase in anti-inflammatory cytokines (IL-1ra, IL-10, and tumor necrosis factor (TNF)-receptor).²⁷ Conversely, after regular training IL-6 basal levels are lower, whereas physically inactive individuals have higher IL-6 basal levels, which reflect chronic systemic low-grade inflammation.²⁷ Exercise enhances the expression of PGC1α (peroxisome-proliferator-activated receptor-γ (PPAR-γ) coactivator 1α), which suppresses the production of ROS and seems to modulate the release of inflammatory cytokines from skeletal muscle.²⁸ Of note, systemic low-grade inflammation has been found to be associated with an increased risk of cardiovascular events and incident cancer.²⁹ During physical activity, higher levels of circulating catecholamines promote leucocyte mobilization and lead to an increased bloodstream concentration of natural killer and lymphocyte T cells, which are effectors of antitumor immune surveillance.³⁰ Overall, chronic moderate-intensity physical activity can inhibit cancer cell proliferation through the regulation of signaling pathways that regulate the immune response.³¹ Regular physical activity reduces insulin-like growth factor (IGF) levels, which contribute to CVD and cancer through several biological effects, such as promoting cell proliferation, inhibiting apoptosis, and inducing angiogenesis.¹⁶ Moreover, physical activity reduces gut exposure to carcinogens by reducing intestinal transit time.³¹ Reductions in obesity and metabolic syndrome are further relevant mechanisms that link physical activity with both reduced CVD and cancer incidence. Strategies aimed at promoting and implementing physical activity should be included in preventive approaches for both CVD and cancer. Indeed, American guidelines for cancer prevention³² and European guidelines for CVD prevention³³ recommend that healthy adults perform 150–300 min of moderate intensity, or 75–150 min of vigorous intensity, activity per week (or a combination of these). Table 3 summarizes practical guideline recommendations for cancer and CVD prevention through a healthy lifestyle.^32,33 Because sedentary behavior is also common in cancer patients and may contribute to their increased risk of CVD, patient-tailored exercise programs have been proposed to improve cardiovascular health in these patients.³⁴

Table 2. Molecular Mechanisms Mediating Lifestyle Effects on Cancer and Atherosclerotic CVD^9,16–28

Mediator	Lifestyle effects	Biological mechanism involved	Effect on cancer pathogenesis	Effects on CVD
Dopamine16,17	Moderate PA raises DA levels in the prefrontal cortex, serum and tumor tissue, overload activity has opposite effects Long-term alcohol intake alters dopamine release	Dopamine 1-like DRs and Dopamine 2-like DRs: G protein-coupled receptors	Modulates apoptosis, cell proliferation and angiogenesis	Mediates antiatherosclerosis effects such as inhibition of macrophage and VSMC proliferation
IGF-1 pathway16,18	Long-term exercise reduces IGF-1 plasma concentrations; obesity and dysregulate IGF-1 pathway	IGF-1 activates several signaling pathways such as PI3K-AKT and MAPK	Induces mitosis, inhibits apoptosis, and impacts cancer cell differentiation	Contributes to atherosclerosis by stimulating VSMC proliferation and migration, extracellular matrix synthesis, and angiogenesis
Adiponectin16,19	Increases after physical training Serum levels are reduced in obesity	Modulates AMP-activated protein kinase signaling, mTOR, and NFκB	Inhibits cell proliferation, induces cell cycle stop and apoptosis	Antiatherogenic properties: inhibits the expression of adhesion molecules, inhibits foam cell formation and VSMC migration and proliferation
ROS20,28	Acute exercise produces ROS, over time regular training activates antioxidant pathways Alcohol and smoking induce increased ROS production	Injures DNA, proteins, and lipids	Causes the production of mutagenic mediators	Contributes to atherosclerosis: leads to endothelial activation, recruits inflammatory cells, promotes migration and proliferation of VSMCs
mTOR16,21	Strength exercise activates mTOR in muscles; endurance exercise inhibits mTOR in muscles, liver, fat, and tumors, and activates mTOR in the heart	Regulates protein synthesis	Promotes cell proliferation	mTOR signaling contributes to: endothelium dysfunction, foam cell formation, VSMC migration and proliferation
SPARC16,22	Exercise increases SPARC expression and secretion	Activates caspase-3 and caspase-8	Stimulates apoptosis	Contributes to myocardial fibrosis; inhibits angiogenesis
BRCA23,24	Sedentary behavior is associated with significantly lower BRCA1 expression	Involved in DNA damage signaling and repair processes	Protects genome integrity in proliferating cells	Protects cardiomyocytes from DNA damage, apoptosis, and heart dysfunction BRCA2 variants are associated with increased serum TC and ApoB levels and increased CVD risk
Nicotine25,26	Assumed with tobacco consumption	Acts via nicotinic acetylcholine receptors, and by increasing VEGF serum levels	Inhibits apoptosis and promotes angiogenesis	Induces endothelial dysfunction and insulin resistance and accelerates atherosclerosis
IL-69,16,20,27	Increases following acute exercise Regular exercise reduces basal IL-6 serum concentrations	Activates JAK-family tyrosine kinases, which induce the MAPK cascade Final effect depends on activated genes of the target cells	Controls cell proliferation and differentiation	Impacts glucose and lipid metabolism and angiogenesis

ApoB, apolipoprotein B; CVD, cardiovascular disease; DR, dopamine receptor; ERK, extracellular signal-regulated kinase; IGF, insulin-like growth factor; IL, interleukin; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K-AKT, phosphatidylinositol 3-kinase/protein kinase B; SPARC, secreted protein acidic and rich in cysteine; ROS reactive oxidative species; TC, total cholesterol; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

Table 3. Practical Recommendations for Cancer and Cardiovascular Disease Prevention With Healthy Lifestyles^32,33

	American guidelines for cancer prevention32	European guidelines for CVD prevention33
Body weight	· Keep body weight within the healthy range and avoid weight gain in adult life	· Recommended that subjects with healthy weight maintain their weight. Recommended that overweight and obese people achieve a healthy weight (or aim to reduce weight)
Physical activity	· Adults should engage in 150–300 min of moderate- intensity PA per week, or 75–150 min of vigorous PA, or an equivalent combination; achieving or exceeding the upper limit of 300 min is optimal 　· Limit sedentary behavior, such as sitting, lying down, watching television, and other forms of screen-based entertainment	· Recommended for healthy adults of all ages to perform at least 150 min/week of moderate intensity or 75 min/week of vigorous intensity aerobic PA or an equivalent combination thereof 　· In healthy adults, a gradual increase in aerobic PA to 300 min/week of moderate intensity or 150 min/week of vigorous intensity aerobic PA, or an equivalent combination thereof, is recommended
Healthy dietary pattern	Includes: 　· Foods that are high in nutrients in amounts that help achieve and maintain a healthy body weight 　· A variety of vegetables – dark green, red, and orange, fiber-rich legumes (beans and peas), and others 　· Fruits, especially whole fruits with a variety of colors 　· Whole grains Limits or does not include: 　· Red and processed meats 　· Sugar-sweetened beverages 　· Highly processed foods and refined grain products	· <5 g of salt per day 　· 30–45 g of fiber per day, preferably from wholegrain products 　· ≥200 g of fruit per day (2–3 servings) 　· ≥200 g of vegetables per day (2–3 servings) 　· Fish 1–2 times per week, one serving of which should be oily 　· 30 g unsalted nuts per day 　· Saturated fatty acids to account for <10% of total energy intake through replacement by polyunsaturated fatty acids 　· Trans unsaturated fatty acids: as little as possible, preferably no intake from processed food, and <1% of total energy intake from natural origin 　· Sugar-sweetened soft drink and alcoholic beverage consumption is discouraged
Alcohol	· It is best not to drink alcohol 　· People who do choose to drink alcohol should limit their consumption to no more than 1 drink per day for women and 2 drinks per day for men	· Alcoholic beverage consumption must be discouraged or limited to 2 glasses per day (20 g/day of alcohol) for men and 1 glass per day (10 g/day of alcohol) for women

CVD, cardiovascular disease; PA, physical activity.

Poor Dietary Patterns

Nutrition is an important contributor to both cardiovascular and cancer risk. The same nutrients that influence CVD also play a role in cancer development. Compelling evidence has shown that greater adherence to a dietary pattern rich in fruits, vegetables, whole grains, and legumes and poor in processed meats and red meat (i.e., a Mediterranean diet), is associated with a lower risk of cancer and CVD incidence/death (with a 6% and 10% risk reduction, respectively).³⁵

Fruits and vegetables contain several nutrients with potentially beneficial effects, including fiber and bioactive substances. Regarding the latter, polyphenols have vasodilator and antiatherogenic effects that seem to be mediated by AMP-activated protein kinase and silent information regulator 1 activation, which lead to increased nitric oxide production, and by the downregulation of the hepatic 3-hydroxy 3-methylglutaryl coenzyme A reductase, which intervenes in a key step of cholesterol biosynthesis.³⁶ Furthermore, due to their anti-inflammatory, antioxidant, and immunomodulatory properties, polyphenols may modulate biological pathways implicated in cancer proliferation.³⁷ However, the global effect of polyphenols in cancer pathogenesis is still controversial.³⁷ Fruits and vegetables, such as whole grains and legumes, are rich in fiber and have beneficial effects on the gut microbiota, which is an emerging target in the prevention and treatment of CVD³⁸ and cancer.³⁹ Processed meat consumption is associated with an increased risk of cardiovascular and cancer death.⁴⁰ This may be due to the high content of saturated fatty acids, which, when consumed in high amounts (>10% energy intake), increase the CVD risk,³³ and to the content of N-nitroso compounds, which are associated with increased rectal cancer incidence.⁴¹ Red meat may also play a role in cardiovascular and cancer pathogenesis through its effect on metabolites produced by the gut microbiome.⁴²

Fat intake and quality contribute to carcinogenesis and CVD. Indeed, trans-fatty acids present in industry-processed foods promote atherosclerosis,⁴³ and may play a pathophysiological role in cancer development due to their pro-inflammatory effects and induction of oxidative stress.⁴⁴ High sodium intake as salt is associated with CVD risk,³³ and seems to promote certain types of cancer, such as gastric cancer.⁴⁵

In clinical practice, improving a harmful dietary pattern is obviously one of the shared measures for prevention of both cancer³² and CVD.³³ The Mediterranean diet may be recommended as a reference dietary pattern in preventive programs.

Tobacco Use

Among the risk factors shared by CVD and cancer, smoking is of particular interest in the field of preventive medicine. Table 4 reports estimated cancer and CVD risk associated with tobacco.^46–50 According to recent reports, smoking is responsible for 30% of all cancer-related deaths in the USA,⁵¹ and for 20% of worldwide deaths due to coronary artery disease.⁵² The pathogenesis of cancer²⁵ and CVD⁵³ involves smoking-related detrimental substances such as ROS, carcinogens, and pro-inflammatory agents, which induce the activation of pathological signaling pathways responsible for both diseases. Detrimental effects of smoking on CVD are mainly mediated by enhanced atherosclerosis due to reduced nitric oxide availability and increased oxidative stress, resulting in lipid peroxidation and vasomotor dysfunction.^26,53 Moreover, even nicotine contributes to the development of cancer and atherosclerosis by inhibiting apoptosis and enhancing angiogenesis.²⁶ Smoking also has prothrombotic effects due to platelet dysfunction and the alteration of antithrombotic, prothrombotic, and fibrinolytic pathways that may precipitate adverse events in CVD and cancer.⁵³ Despite the established benefits of smoking cessation, clinical practice experience shows that it is particularly challenging for patients to quit. Counseling and pharmacological assistance are both useful strategies for smoking cessation.⁵⁴

Table 4. Cancer and CVD Risk Associated With Tobacco Smoke^46–50

	Estimated risk	95% CI
Cancer site*
Oral	3.43	2.37–4.94
Esophageal	2.50	2.00–3.13
Upper digestive tract	3.57	2.63–4.84
Stomach	1.64	1.37–1.95
Pancreas	1.70	1.51–1.91
Liver	1.56	1.29–1.87
Nasal-sinuses, nasopharingeal	1.95	1.31–2.91
Pharyngeal	6.76	2.86–6.0
Laryngeal	6.98	3.14–15.5
Lung	8.96	6.73–12.1
Kidney	1.52	1.33–1.74
Lower urinary tract	2.77	2.17–3.54
Cervix	1.83	1.51–2.21
CVD
Atrial fibrillation#	1.32	1.12–1.57
Myocardial infarction**	2.95	2.77–3.14
Heart failure§	1.75	1.54–1.99
Stroke&	1.70	1.29–2.23

*Risk ratio of current vs. never smokers and cancer reported in a meta-analysis including cohort and case-control studies. Data from Gandini et al.^{46 #}Risk ratio of current vs. never smokers and incident atrial fibrillation reported in a meta-analysis including cohort studies (388,030 participants). Data from Aune et al.⁴⁷ **Odds ratio of nonfatal myocardial infarction in current smokers compared with never smokers in a case-control study (27,089 participants). Data from Teo et al.^{48 §}Adjusted relative risk of current vs. never smokers reported in a meta-analysis of prospective studies (3,803,792 participants). Data from Aune et al.^{49 &}Risk ratio of current vs. never smokers and incident stroke in a cohort study (22,516 participants). Data from Myint et al.⁵⁰ CI, confidence interval; CVD, cardiovascular disease.

Alcohol Abuse

The effects of alcohol on the cardiovascular system^55–58 and cancer pathogenesis²⁰ have been extensively investigated.^59,60 About 6% of cancer cases are related to alcohol consumption,⁶¹ with a dose-risk relationship observed for several cancers.⁶² Alcohol abuse has been reported to be associated with increased CVD risk, with a more than 2-fold increased risk of atrial fibrillation and congestive heart failure and a 1.45-fold increased risk of myocardial infarction.⁵⁶ Of note, smoking and alcohol abuse together lead to an even more than additive and dose-related increase in CVD and cancer risk.⁴⁶

Alcohol acts as a solvent for tobacco-related carcinogens and is associated with increased production of nitrogen and ROS.⁵⁹ These latter 2 effects may contribute to the development of cancer and CVD. High alcohol intake also increases diabetes risk, which is a condition that may promote cancer and CVD.⁶³ Additional mechanisms through which alcohol abuse may increase CVD risk include blood pressure increase due to sympathetic nervous system and renin-angiotensin-aldosterone system activation, with an overall imbalance of vasoconstrictor and vasodilator mediators,⁵⁵ and high circulating cholesterol levels, which have been found to be associated with binge drinking intensity.⁶⁴ Smoking and alcohol use during adolescence is associated with early vascular damage, with potential reversibility of arterial changes by discontinuing these behaviors.⁶⁵

Restrictive alcohol policies have been found to be effective in preventing cancer development and reducing cancer-related mortality. In a recent USA study, stronger alcohol policies were associated with an 8.5% decrease in alcohol-attributable cancers.⁶⁶ It is important to inform people that alcohol abuse increases CVD and cancer risk. Assessment of alcohol misuse severity is crucial in establishing appropriate treatment interventions.⁶⁷ Comprehensive alcohol treatment programs should include psychoeducational interventions and should address psychosocial risk factors.⁶⁷

Obesity

Epidemiological and pathophysiological studies have shown a consistent association between obesity and the development of CVD and cancer (Table 5).^68–71 Over the past decades, a continuous increase in obesity rates has been observed worldwide, contributing to the growing burden of CVD and cancer. It has been estimated that 14% of cancer deaths in men and 20% of those in women may be attributed to overweight and obesity.⁷²

Table 5. Cancer and CVD Risk Associated With Obesity in Males and Females^68–71

	Estimated risk	95% CI
Cancer site*
Esophageal (F)	2.04	1.18–3.55
Gallbladder (F)	1.82	1.32–2.50
Gallbladder (M)	1.47	1.17–1.85
Pancreatic (M)	1.36	1.07–1.73
Pancreatic (F)	1.34	1.22–1.46
Colon (M)	1.57	1.48–1.65
Colon (F)	1.19	1.04–1.36
Kidney (F)	1.72	1.58–1.88
Kidney (M)	1.57	1.38–1.77
Postmenopausal breast	1.25	1.07–1.46
Endometrial	1.85	1.30–2.65
Leukemia (F)	1.32	1.08–1.60
Malignant melanoma (M)	1.26	1.07–1.48
Non-Hodgkin’s lymphoma (F)	0.91	0.86–0.97
Multiple myeloma (M)	0.58	0.36–0.93
CVD
Atrial fibrillation#	1.51	1.35–1.68
Myocardial infarction**	1.77	1.59–1.97
Heart failure ***	3.74	3.24–4.31
Stroke***	1.75	1.40–2.20

*Pooled risk ratios of obese individuals (defined on the basis of BMI) compared with individuals with a normal BMI in a meta-analysis of 57 observational studies. Data from Dobbins et al.^{68 #}Pooled risk ratio of obese individuals vs. non-obese individuals in a meta-analysis of cohort studies including 587,372 subjects. Data from Asad et al.⁶⁹ **Odds ratio for top waist quintile vs. bottom quintile in a case-control study including 27,000 participants. Data from Yusuf et al.⁷⁰ ***Hazard ratios for severe obesity (BMI ≥35) vs. normal weight in the Atherosclerosis Risk in Communities (ARIC) study including 13,730 participants. Data from Ndumele et al.⁷¹ BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease.

Several factors, including dietary pattern, physical activity, metabolic pathways, hormone activity, inflammation, and oxidative stress, contribute to both the development and progression of CVD and cancer in obese individuals. Insulin/IGF-1, IL-6, and leptin, which are increased in obese patients, activate multiple biological pathways that may explain this association (Figure 2).¹⁸ Adipose tissue releases cytokines, known as adipokines, that have immunomodulatory effects and regulate gene expression. These mediators seem to link obesity with both CVD and cancer. Adipokines may be involved in tumorigenesis by interfering with the balance of anti-tumoral and pro-oncogenic microRNAs. For example, adiponectin, leptin, and resistin induce the expression of miR-21,⁷³ which is a tumorigenesis regulator⁷⁴ and may also be involved in the pathogenesis of hypertension.⁷⁵ In addition to IL-6, several pro-inflammatory cytokines, including TNF-α and IL-1β, have been shown to be upregulated in obese patients and can contribute to a pro-oncogenic microenvironment and atherogenesis. Insulin and IGF-1 hormones are further mediators with mitogenic effects that contribute to atherosclerosis and cancer cell proliferation in obese individuals. Signaling pathways activated by these hormones include Janus kinase/signal transducers and activators of transcription, mitogen-activated protein kinase, and phosphatidyl-inositol 3-kinase, which stimulate cell proliferation, promote cell migration and stemness, and inhibit apoptosis, all effects that play a crucial role in oncogenesis.⁶¹ The renin-angiotensin system, a biological pathway with an established role in CVD pathogenesis whose components are overexpressed in adipose tissue, may also affect the tumor microenvironment by promoting angiogenesis and cell migration and inhibiting apoptosis.⁷⁶ Of note, obesity is also associated with a higher prevalence of clonal hematopoiesis of indeterminate potential, which is an emerging risk factor for CVD and hematologic malignancies.⁷⁷

Figure 2.

Main obesity-related molecular pathways that contribute to CVD and cancer.¹⁸ AKT, protein kinase B; CVD, cardiovascular disease; ERK, extracellular signal-regulated kinase; IR, insulin receptor; IGF1, insulin-like grow factor; IGF-R, IGF receptor; JAK/STAT, Janus kinase/signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; ObR, leptin receptor; PI3K, phosphatidylInositol 3-kinase.

Lifestyle interventions aimed at weight loss will reduce cancer^78,79 and CVD risk,³³ and thus must be included in preventive and tailored treatment strategies. In the clinical management of obesity, body mass index and waist circumference should be used to guide the efficacy of weight loss measures, because they are associated with cardiometabolic disease⁸⁰ and cancer.³² In order to prevent CVD and cancer through the achievement and maintenance of a healthy body weight, the dietary pattern should limit global caloric intake, saturated fats, sugar, and salt and include a variety of fruits and vegetables.^32,33

Executive Summary

Considering the large body of evidence on the increased CVD and cancer risk associated with an unhealthy lifestyle, comprehensive preventive strategies should intervene in all habits that expose individuals to an increased risk of disease. The first step is to counsel individuals to recognize the importance of lifestyle in global health. To establish a tailored preventive approach, the current individual clinical state must be assessed and unhealthy behaviors identified. Physical activity level should be evaluated, and the favorable effects of regular physical activity as recommended by guidelines on cancer³² and CVD prevention³³ should be emphasized. Nutritional education aimed at teaching the basis of a healthy dietary pattern is a further cornerstone in CVD^33,54 and cancer prevention.²⁶ Other main components of a global preventive approach should be counseling on smoking cessation⁵⁴ and rehabilitative programs for alcohol abuse.⁶⁷

Conclusions

Increased knowledge regarding the pathophysiological mechanisms linking CVD and cancer due to cardiovascular risk factors, such as unhealthy lifestyle behaviors, will help clarify the reverse cardio-oncology phenomenon that highlights the inherent cancer risk in patients with CVD.¹¹ In this review, we have discussed diverse biological pathways that contribute to CVD development and are also involved in cancer pathogenesis. Interventions able to modify behaviors known to contribute to CVD may have additional benefits in terms of reduced cancer risk and vice versa. In this review, we emphasize the role of a comprehensive preventive approach starting from an individual lifestyle assessment that is aimed at managing unhealthy behaviors through improved nutrition, smoking cessation, alcohol abuse counseling, physical activity, and weight management. This multimodal approach is well established for CVD patients⁵⁴ and has recently been proposed to improve cardiovascular outcomes even in cancer patients.^81,82 Increased effort in the early implementation of primary prevention with measures that promote a healthy lifestyle from childhood will result in a larger health benefit by reducing both CVD and cancer risk in the long term, as well as the costs associated with them.

Disclosures

The authors declare that there are no conflicts of interest.

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