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The “common soil hypothesis”: Evidence from population studies?
Thrombosis Research 125 Suppl. 2 (2010) S92–S95
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
The “common soil hypothesis”: Evidence from population studies? Maria Benedetta Donati* Research Laboratories, “John Paul II” Centre for High Technology Research and Education in Biomedical Science, Catholic University, Campobasso, Italy
article info Keywords: Common soil Hormone-dependent tumors Cardiovascular ischemic disease Moli-sani study
Introduction Cardiovascular disease (CVD) and cancer are responsible for 3 out of 4 deaths in western countries and for the vast majority of morbility and disabilities in our society. We have proposed some years ago [1– 3], and evidence is presently accumulating, that ischemic CVD and several forms of tumors (hormone-dependent tumors and tumors of the gastrointestinal tract) share some common mechanisms, as if they were two branches from the same tree or two trees emerging from the same piece of earth, with intermingled roots. Schematically, the pieces of evidence for the existence of a possible “common soil” in the pathogenesis of ischemic CVD and the above mentioned tumors can be grouped in three levels: Cellular/Molecular level Several mechanisms have been recognized to play a crucial role in the growth and migration of both tumor and vascular cells as suggested in a provocative editorial in 2001 where the authors wonder whether “atherosclerosis” could be defined ”a cancer of blood vessels” [4]. Indeed, the most widely studied inducers of cellular responses, such as oxidative stress, proliferation regulatory pathways, altered expression of proteases, ligand / growth factor interactions, triggers of enhanced nuclear transcription or of processes such as cell migration and angiogenesis, have been described to act both in pathways of vascular-reaction-to-injury and in processes of malignant cell proliferation. If one would like to give a schematic representation of all these processes, inflammatory responses should be considered as a general bridge between cellular processes related to atherosclerosis and to malignant (cells and cytokines) proliferation. Let us take the example of a * Correspondence: Maria Benedetta Donati, MD, PhD. Scientific Coordinator, Research Laboratories, “John Paul II” Centre for High Technology Research, and Education in Biomedical Science, Catholic University, Largo Gemelli, 1, 86100 Campobasso, Italy. Tel.: +39-0874-312278; fax.: +39-0874-312710. E-mail address: [email protected] (M.B. Donati) 0049-3848 /$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
nuclear transcription factor such as NF-kappaB. The latter, has been described as a tumor promoter in inflammation-associated cancer [5] and is also central to the recognized mechanisms leading to Tissue Factor (TF) expression following, f.i., stimulation with bacterial lipopolysaccharide [6,7]. TF, a pivotal protein in the activation of the clotting cascade and a signalling mediator in cancer cell migration and angiogenesis, represents a paradigm for the “common soil” hypothesis [8]. Indeed, we could demonstrate that both human monocytes and cells from a highly metastatic human breast carcinoma line were able to express TF in response to leptin, a well recognized mediator of obesity [9–11]. These observations provide not only a cellular model supporting the common soil hypothesis, but also offer biological plausibility to the role of obesity as an intermediate phenotype for both hormone dependent cancers and cardiovascular ischemic diseases [12]. Among typical ingredients of the main components of the Mediterranean diet, resveratrol and related flavonoids are natural products derived from grapes and present in wine: resveratrol has been described as a cancer chemopreventive agent with both antitumor and anti-inflammatory effects [13]. Resveratrol has also been studied together with quercetin as a down-regulator of TF expression by stimulated monocytes or endothelial cells and its effect found to be mediated by an inhibition of the NF-kappaB pathway [7]. Pharmacological level Studies on the role of the hemostatic system in tumor growth and metastases started many decades ago with a number of experimental models, particularly in mice, where antithrombotic drugs were shown to control the development of tumors, both in classical models used for screening of chemotherapeutic agents, such as the Lewis Lung Carcinoma or the B16 melanoma, and on nude or SCID mice implanted with human tumors [14,15]. Indeed, at the experimental level, evidence had been collected to suggest that modification of the host’s haemostatic system by differ-
M.B. Donati / Thrombosis Research 125 (2010) S92–S95
ent pharmacological approaches could lead to changes in the degree and speed of tumor and metastasis growth [16–18]. The data could be schematically summarized as follows: whatever antithrombotic drug or condition, such as antiplatelet antibodies or dysfunctional platelets, would reduce blood cell stickiness and/or increase blood fluidity, would also delay and reduce the trapping of tumor cells within the lungs of the host by diverting cancer cells towards the spleen or the liver, to be destroyed there by the reticulo-endothelial system. As a result, the subsequent growth of lung metastasis would be significantly delayed or inhibited [16–20]. These data did not find initially any translation into clinical applications. One of the major difficulties to prove the effectiveness of anticoagulants in cancer patients was that the use of antivitamin K drugs – remarkably effective in some animal models [17,21,22] – required laboratory monitoring and induced serious haemorrhagic risk in patients with cancer, who are often thrombocytopenic due to chemotherapy and/or radiotherapy. The development of lowmolecular-weight heparins (LMWH) in the prevention/treatment of thrombosis in cancer patients, has lately made available a more patient-friendly antithrombotic treatment in these patients. The favorable experience with LMWH opened indeed the way to new trials with heparins to modify the natural history of several tumors [23,24]. This happened during the last few years and is still going on. From preliminary data available in the first trials [25–28] it would appear that LMWH treatment could delay metastasis growth in different tumors, but particularly if the tumor is still at an early stage. This finding, confirmed by trials with different design and treatment schedules [25–28], may be explained by the following hypothesis: LMWH would act on the dissemination of tumor cells by anti-adhesive/anti-inflammatory properties (different at least in part from their anticoagulant activity); these properties would enable LMWH to prevent the adhesion of tumor cells to the vascular wall and their extravasation to form metastatic foci. Once metastases have been formed, however, LMWH would be unable to prevent their growth. For this reason only tumors at a relatively early stage, i.e. with still a significant burden of circulating tumor cells, would respond to the inhibitory or delaying effects of LMWH. This hypothesis is supported by recent in vitro data showing the ability of some LMWH to prevent cell/cell interactions, relevant for the adhesion of cancer cells to the vascular wall and subsequent extravasation [29,30]. Besides oral or parenteral anticoagulants, other major classes of drugs used to prevent primary or secondary thrombotic events, such as aspirin and other NSAIDs or statins have been suggested to prevent tumor development; aspirin would be active under specific conditions (colorectal cancer and estrogen positive breast cancer), while for statins the results await further confirmation [31–33]. Epidemiological level This level has many connections with the above mentioned biological and pharmacological pieces of evidence and is particularly relevant since the clear demonstration of common risk factors for ischemic CVD and tumors could lead to the possibility of a wider approach in prevention strategies. The risk for morbidity and mortality from CVD is known to follow a geographic gradient: if one consider f.i. Europe, its Southern Countries, such as Italy, Spain, Greece show a protection from CV mortality with figures which may be, according to the different studies, from 3- to 5-fold lower than in Northern European Countries [34]. This gradient has been ascribed, besides ethnical/genetic factors, to the life and particularly dietary habits in the different countries considered, with an advantage for Southern Countries where a “Mediterranean” style diet has been so far more extensively followed.
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Although less known, a gradient is observed also for the overall incidence of gastrointestinal and hormone-dependent cancers (large bowel, breast, endometrium, prostate) which is lower in Mediterranean Countries than in Scandinavia, UK or USA. Again, the Mediterranean style diet has been implicated and a calculation made that a relevant fraction of cancer occurrence (10 to 25%) in highly developed Western Countries could be avoided with a closer adherence to healthy Mediterranean diet [35]. The typical components of Mediterranean dietary habits (fruits and vegetables, fish, unrefined cereals, olive oil and wine in moderation) represent some of the main risk/protection factors of the “common soil”, together with components of the metabolic syndrome and other intermediate phenotypes, such as obesity, insulin resistance and sedentary life. The role of single elements of the Mediterranean diet, already well known for their impact on cardiovascular risk, has been evaluated during the nineties for their risk/protection profile in different types of cancer with a number of case-control studies in Italy, by Carlo La Vecchia and his group [36]. Few years later, in 2003, a pivotal study [37], showed in a Greek population of over 22,000 adults, prospectically followed for a median followup of 44 months, that higher adherence to mediterranean diet (measured by an appropriate score) implied protection, not only from cardiovascular mortality (33%) but also from cancer mortality (25%). Some more recent studies confirmed these effects, till 2008 when a meta-analysis of 6 cohort studies, performed by an Italian group, showed that a 2-point increase in a mediterranean diet score significantly reduced the incidence or mortality from both ischemic CVD and cancer [38]. Among tumors considered as involved in the “common soil” hypothesis, already breast and colorectal cancer have been considered separately [39,40] in cohort studies where it appeared that higher adherence to mediterranean diet was associated with a reduced risk; on the other hand, just few days ago results of the EPIC study were published to indicate that also the risk for incident gastric carcinoma is significantly reduced by a closer adherence to the mediterranean diet [41]. Gastrointestinal malignancies and particularly colorectal cancer has been reported more prevalent in patients undergoing coronary angiography for coronary artery disease; the association between the presence of advanced colonic lesions and CVD was stronger in the group with metabolic syndrome and history of smoking [42]. Intermediate phenotypes, such as the metabolic syndrome and diabetes, are increasingly found in close association with both CVD and hormone dependent tumors: evidence is particularly growing for diabetes, as suggested, among others, by a large-scale population-based cohort study in Japan, where, in nearly 100,000 adult subjects, followed up for about 10 years, the total cancer risk was 27% higher in diabetic patients [43]. Reduced insulin sensitivity with compensatory hyperinsulinemia and elevated levels of IGF-1 would stimulate abnormal cell proliferation in different sites [43]. The Moli-sani study On top of the case-control and retrospective studies, a prospective evaluation of the “common soil” hypothesis in an Italian context was badly needed; this prompted us, 6–7 years ago, to plan the Moli-sani project, a randomized prospective cohort study in the Molise region, to investigate gene/environment interactions in the risk of ischemic CVD and tumors. So far, the majority of studies on the identification of risk factors for atherothrombotic disease and malignancies had been conducted in Northern Europe or the USA, with few exceptions for regions of Northern Italy. The Moli-sani project, which aims at recruiting 25,000 adults (older than 35 years, with no upper age limit) randomised from the city-hall registries, has almost completed its cross-sectional phase (24,400 subjects recruited at the end of January 2010)
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M.B. Donati / Thrombosis Research 125 (2010) S92–S95
and will soon start the follow-up, which includes monitoring not only mortality and morbility for cardiovascular ischemic events and malignant events, but also for those intermediate phenotypes such as diabetes, insulin resistance, obesity, metabolic syndrome which are increasingly considered a predisposing condition for both CVD and hormone-dependent or gastro-intestinal tumors [44]. Moreover, the thorough investigation of life habits and particularly of dietary habits/physical exercise administered to each subject at recruitment, will allow us to correlate the events recorded at follow-up with the most important environmental risk factors for both types of the major killers of our society. Special focus has been addressed to dietary habits through an extremely detailed questionnaire (modified from the EPIC questionnaire to fit with the regional dietary habits) which has already provided useful pieces of information on the degree of adherence to Mediterranean diet of our population and on dietary patterns which correlate with the main risk/protection factors for cardiovascular disease and inflammatory chronic conditions [45,46]. Gene/environment interactions in the determination of disease risk will be evaluated during the follow-up when the appropriate samples collected in the Moli-sani biobank will be used for genetic studies. Indeed, the biological bank of the project will ultimately contain 700,000 biological samples, stored in liquid nitrogen and protected by the most sophisticated technologies (two batches of 14 “paillettes” per subject). Markers related to inflammation and activation of thrombogenesis will be primarily studied as tools to better clarify the link between risk factors of the “common soil”. Conclusions We are confident that the Moli-sani study, with its multiple pieces of information at cross-sectional and with its specific follow-up for both cancer and CVD events, will be well suited to answer the fascinating question whether the “common soil“ hypothesis is more than an hypothesis. Competing interests: The author states she has no conflict of interest in relation to this manuscript. References 1. Donati MB. Cancer and cardiovascular disease: does a common soil exist? Pathophysiol Haemost Thromb 2003;33(suppl 2):1. 2. Donati MB. Thrombosis and cancer: A personal view. Thromb Haemost 2007; 98:126–8. 3. Iacoviello L, Santimone I, Latella MC, de Gaetano G, Donati MB. Nutrigenomics: a case for the common soil between cardiovascular disease and cancer. Genes Nutr 2008;3:19–24. 4. Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS. Atherosclerosis: a cancer of the blood vessels? Am J Clin Pathol 2001;116(Suppl):S97–107. 5. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461–6. 6. Napoleone E, Di Santo A, Camera M, Tremoli E, Lorenzet R. Angiotensinconverting enzyme inhibitors downregulate tissue factor synthesis in monocytes. Circ Res 2000;86:139–43. 7. Di Santo A, Mezzetti A, Napoleone E, et al. Resveratrol and quercetin downregulate tissue factor expression by human stimulated vascular cells. J Thromb Haemost 2003;1:1089–95. 8. Donati MB, Falanga A, Lorenzet R. Cancer and thrombosis: a two way interaction. In: Thrombosis. Fundamental and clinical aspects. Leuven University Press, 2003: pp. 417–31. 9. Napoleone E, Zurlo F, Latella MC, et al. Paclitaxel downregulates tissue factor in cancer and host tumor-associated cells. Eur J Cancer 2009;45:470–7. 10. Napoleone E, Di Santo A, Amore C, et al. Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk? J Thromb Haemost 2007;5:1462–68. 11. Napoleone E, Cutrone A, Zurlo F, et al. Leptin enhances tissue factor synthesis in the human breast cancer cell line MCF7. [abstr. PP-MO-481]. XXII Congress ISTH, 2009, Boston. 12. Gaziano JM. Fifth phase of the epidemiologic transition: the age of obesity and inactivity. JAMA 2010;303:275–6.
13. Jang M, Cai L, Udeani G O, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;275:218–20. 14. Poggi A, Polentarutti N, Donati MB, et al. Blood coagulation changes in mice bearing Lewis lung carcinoma, a metastasizing tumor. Cancer Res 1977;37:272–7. 15. Bani MR, Falanga A, Alessio MG, et al. Blood coagulation changes in nude mice bearing human colon carcinomas. Int J Cancer 1992;50: 75–9. 16. Mussoni L, Poggi A, de Gaetano G, et al. Effect of ditazole, an inhibitor of platelet aggregation, on a metastasizing tumour in mice. Br J Cancer 1978;37:126–9. 17. Poggi A, Mussoni L, Kornblihtt L, et al. Warfarin enantiomers, anticoagulation, and experimental tumor metastasis. Lancet 1978;1: 163–4. 18. Chmielewska J, Poggi A, Janik P, et al. Effect of defibrination with batroxobin on growth and metastasis of JW sarcoma in mice. Eur J Cancer 1980;16:919–23. 19. Donati MB, Poggi A. Malignancy and haemostasis. Br J Haematol 1980;44: 173–82. 20. Poggi A, Donati MB, Garattini S. Fibrin and cancer cell growth: Problems in the evaluation of experimental models. In: Malignancy and the hemostatic system, Raven Press, New York, 1981:pp 89–101. 21. Poggi A, Mussoni L, Kornblihtt L, et al. Warfarin enantiomers, anticoagulation, and experimental tumor metastasis. Lancet 1978;1:163–4. 22. Roncaglioni MC, D’Alessandro AP, Casali B, et al. Gamma-glutamyl carboxylase activity in experimental tumor tissues: a biochemical basis for vitamin K dependence of cancer procoagulant. Haemostasis 1986;16:295–9. 23. Falanga A. The effect of anticoagulant drugs on cancer. J Thromb Haemost 2004; 2:1263–5. 24. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53. 25. Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266–71. 26. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin therapy with dalteparin and survival in advanced cancer: the framing advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004;22:1944–8. 27. Klerk CP, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130–5. 28. Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123–2129. 29. Maugeri N, de Gaetano G, Barbanti M, et al. Prevention of plateletpolymorphonuclear leukocyte interactions: new clues to the antithrombotic properties of parnaparin, a low molecular weight heparins. Haematologica 2005;90:815–21. 30. Maugeri N, Di Fabio G, Barbanti M, et al. Parnaparin, a low molecular weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost 2007;97: 965–73. 31. Elwood PC, Gallagher AM, Duthie GG, et al. Aspirin, salicylates and cancer. Lancet, 2009;373:1301–9. 32. Cuzik J, Otto F, Baron JA, et al. Aspirin and non-stroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 2009; 10:501–7. 33. Holmes MD, Chen WY, Li L, et al. Aspirin intake and survival after breast cancer.2010 J Clin Oncol. published ahead of print February 17. 34. Tunstall-Pedoe H, Kuulasma K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999;353: 1547–57. 35. Trichopoulou D, Lagiou P. Dietary patterns and mortality. Brit J Nutr 2001;85: 133–4 36. La Vecchia C, Chatenoud L, Altieri A, Tavani A. Nutrition and Health: epidemiology of diet, cancer and cardiovascular disease in Italy. Nutr Metab Cardiovasc Dis 2001;11(suppl 4):10–5. 37. Trichopoulou A, Costacou T, Bamia C, Trichopoulou D. Adherence to a mediterranean diet and survival in a greek population. N Engl J Med 2003;348:2599–608. 38. Sofi F, Cesari F, Abbate R et al. Adherence to Mediterranean diet and health status: meta-analysis. Brit Med J 2008;337:1334–41. 39. Fung TT, Hu FB, McCullough ML, et al. Diet quality is associated with the risk of estrogen receptor-negative breast cancer in postmenopausal women. J Nutr 2006;136:466–72. 40. Reedy J, Mitrou PN, Krebs-Smith SM, et al. Index-based dietary patterns and risk of colorectal cancer: the NIH-AARP Diet and Health Study. Am J Epidemiol 2008;168:38–48. 41. Buckland G, Agudo A, Lujan ´ L, et al. Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Am J Clin Nutr 2010;91:381–90. 42. Chan AO, Jim MH, Lam KF, et al. Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA 2007;298: 1412–9.
M.B. Donati / Thrombosis Research 125 (2010) S92–S95 43. Inoue M, Iwasaki M, Otani T, et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 2006 Sep 25;166(17):1871–7. 44. Iacoviello L, Bonanni A, Costanzo S, et al; on behalf of the Moli-sani Project Investigators: The Moli-sani Project, a randomized, prospective cohort study in the Molise region in Italy; design, et al. Ital J Public Health 2007;4:110–8.
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45. Centritto F, Iacoviello L, di Giuseppe R, et al; Moli-sani Investigators. Dietary patterns, cardiovascular risk factors and C-reactive protein in a healthy Italian population. Nutr Metab Cardiovasc Dis 2009;19:697–706. 46. di Giuseppe R, Di Castelnuovo A, Centritto F, et al. Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. J Nutr. 2008;138:1939–45.
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
The “common soil hypothesis”: Evidence from population studies? Maria Benedetta Donati* Research Laboratories, “John Paul II” Centre for High Technology Research and Education in Biomedical Science, Catholic University, Campobasso, Italy
article info Keywords: Common soil Hormone-dependent tumors Cardiovascular ischemic disease Moli-sani study
Introduction Cardiovascular disease (CVD) and cancer are responsible for 3 out of 4 deaths in western countries and for the vast majority of morbility and disabilities in our society. We have proposed some years ago [1– 3], and evidence is presently accumulating, that ischemic CVD and several forms of tumors (hormone-dependent tumors and tumors of the gastrointestinal tract) share some common mechanisms, as if they were two branches from the same tree or two trees emerging from the same piece of earth, with intermingled roots. Schematically, the pieces of evidence for the existence of a possible “common soil” in the pathogenesis of ischemic CVD and the above mentioned tumors can be grouped in three levels: Cellular/Molecular level Several mechanisms have been recognized to play a crucial role in the growth and migration of both tumor and vascular cells as suggested in a provocative editorial in 2001 where the authors wonder whether “atherosclerosis” could be defined ”a cancer of blood vessels” [4]. Indeed, the most widely studied inducers of cellular responses, such as oxidative stress, proliferation regulatory pathways, altered expression of proteases, ligand / growth factor interactions, triggers of enhanced nuclear transcription or of processes such as cell migration and angiogenesis, have been described to act both in pathways of vascular-reaction-to-injury and in processes of malignant cell proliferation. If one would like to give a schematic representation of all these processes, inflammatory responses should be considered as a general bridge between cellular processes related to atherosclerosis and to malignant (cells and cytokines) proliferation. Let us take the example of a * Correspondence: Maria Benedetta Donati, MD, PhD. Scientific Coordinator, Research Laboratories, “John Paul II” Centre for High Technology Research, and Education in Biomedical Science, Catholic University, Largo Gemelli, 1, 86100 Campobasso, Italy. Tel.: +39-0874-312278; fax.: +39-0874-312710. E-mail address: [email protected] (M.B. Donati) 0049-3848 /$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
nuclear transcription factor such as NF-kappaB. The latter, has been described as a tumor promoter in inflammation-associated cancer [5] and is also central to the recognized mechanisms leading to Tissue Factor (TF) expression following, f.i., stimulation with bacterial lipopolysaccharide [6,7]. TF, a pivotal protein in the activation of the clotting cascade and a signalling mediator in cancer cell migration and angiogenesis, represents a paradigm for the “common soil” hypothesis [8]. Indeed, we could demonstrate that both human monocytes and cells from a highly metastatic human breast carcinoma line were able to express TF in response to leptin, a well recognized mediator of obesity [9–11]. These observations provide not only a cellular model supporting the common soil hypothesis, but also offer biological plausibility to the role of obesity as an intermediate phenotype for both hormone dependent cancers and cardiovascular ischemic diseases [12]. Among typical ingredients of the main components of the Mediterranean diet, resveratrol and related flavonoids are natural products derived from grapes and present in wine: resveratrol has been described as a cancer chemopreventive agent with both antitumor and anti-inflammatory effects [13]. Resveratrol has also been studied together with quercetin as a down-regulator of TF expression by stimulated monocytes or endothelial cells and its effect found to be mediated by an inhibition of the NF-kappaB pathway [7]. Pharmacological level Studies on the role of the hemostatic system in tumor growth and metastases started many decades ago with a number of experimental models, particularly in mice, where antithrombotic drugs were shown to control the development of tumors, both in classical models used for screening of chemotherapeutic agents, such as the Lewis Lung Carcinoma or the B16 melanoma, and on nude or SCID mice implanted with human tumors [14,15]. Indeed, at the experimental level, evidence had been collected to suggest that modification of the host’s haemostatic system by differ-
M.B. Donati / Thrombosis Research 125 (2010) S92–S95
ent pharmacological approaches could lead to changes in the degree and speed of tumor and metastasis growth [16–18]. The data could be schematically summarized as follows: whatever antithrombotic drug or condition, such as antiplatelet antibodies or dysfunctional platelets, would reduce blood cell stickiness and/or increase blood fluidity, would also delay and reduce the trapping of tumor cells within the lungs of the host by diverting cancer cells towards the spleen or the liver, to be destroyed there by the reticulo-endothelial system. As a result, the subsequent growth of lung metastasis would be significantly delayed or inhibited [16–20]. These data did not find initially any translation into clinical applications. One of the major difficulties to prove the effectiveness of anticoagulants in cancer patients was that the use of antivitamin K drugs – remarkably effective in some animal models [17,21,22] – required laboratory monitoring and induced serious haemorrhagic risk in patients with cancer, who are often thrombocytopenic due to chemotherapy and/or radiotherapy. The development of lowmolecular-weight heparins (LMWH) in the prevention/treatment of thrombosis in cancer patients, has lately made available a more patient-friendly antithrombotic treatment in these patients. The favorable experience with LMWH opened indeed the way to new trials with heparins to modify the natural history of several tumors [23,24]. This happened during the last few years and is still going on. From preliminary data available in the first trials [25–28] it would appear that LMWH treatment could delay metastasis growth in different tumors, but particularly if the tumor is still at an early stage. This finding, confirmed by trials with different design and treatment schedules [25–28], may be explained by the following hypothesis: LMWH would act on the dissemination of tumor cells by anti-adhesive/anti-inflammatory properties (different at least in part from their anticoagulant activity); these properties would enable LMWH to prevent the adhesion of tumor cells to the vascular wall and their extravasation to form metastatic foci. Once metastases have been formed, however, LMWH would be unable to prevent their growth. For this reason only tumors at a relatively early stage, i.e. with still a significant burden of circulating tumor cells, would respond to the inhibitory or delaying effects of LMWH. This hypothesis is supported by recent in vitro data showing the ability of some LMWH to prevent cell/cell interactions, relevant for the adhesion of cancer cells to the vascular wall and subsequent extravasation [29,30]. Besides oral or parenteral anticoagulants, other major classes of drugs used to prevent primary or secondary thrombotic events, such as aspirin and other NSAIDs or statins have been suggested to prevent tumor development; aspirin would be active under specific conditions (colorectal cancer and estrogen positive breast cancer), while for statins the results await further confirmation [31–33]. Epidemiological level This level has many connections with the above mentioned biological and pharmacological pieces of evidence and is particularly relevant since the clear demonstration of common risk factors for ischemic CVD and tumors could lead to the possibility of a wider approach in prevention strategies. The risk for morbidity and mortality from CVD is known to follow a geographic gradient: if one consider f.i. Europe, its Southern Countries, such as Italy, Spain, Greece show a protection from CV mortality with figures which may be, according to the different studies, from 3- to 5-fold lower than in Northern European Countries [34]. This gradient has been ascribed, besides ethnical/genetic factors, to the life and particularly dietary habits in the different countries considered, with an advantage for Southern Countries where a “Mediterranean” style diet has been so far more extensively followed.
S93
Although less known, a gradient is observed also for the overall incidence of gastrointestinal and hormone-dependent cancers (large bowel, breast, endometrium, prostate) which is lower in Mediterranean Countries than in Scandinavia, UK or USA. Again, the Mediterranean style diet has been implicated and a calculation made that a relevant fraction of cancer occurrence (10 to 25%) in highly developed Western Countries could be avoided with a closer adherence to healthy Mediterranean diet [35]. The typical components of Mediterranean dietary habits (fruits and vegetables, fish, unrefined cereals, olive oil and wine in moderation) represent some of the main risk/protection factors of the “common soil”, together with components of the metabolic syndrome and other intermediate phenotypes, such as obesity, insulin resistance and sedentary life. The role of single elements of the Mediterranean diet, already well known for their impact on cardiovascular risk, has been evaluated during the nineties for their risk/protection profile in different types of cancer with a number of case-control studies in Italy, by Carlo La Vecchia and his group [36]. Few years later, in 2003, a pivotal study [37], showed in a Greek population of over 22,000 adults, prospectically followed for a median followup of 44 months, that higher adherence to mediterranean diet (measured by an appropriate score) implied protection, not only from cardiovascular mortality (33%) but also from cancer mortality (25%). Some more recent studies confirmed these effects, till 2008 when a meta-analysis of 6 cohort studies, performed by an Italian group, showed that a 2-point increase in a mediterranean diet score significantly reduced the incidence or mortality from both ischemic CVD and cancer [38]. Among tumors considered as involved in the “common soil” hypothesis, already breast and colorectal cancer have been considered separately [39,40] in cohort studies where it appeared that higher adherence to mediterranean diet was associated with a reduced risk; on the other hand, just few days ago results of the EPIC study were published to indicate that also the risk for incident gastric carcinoma is significantly reduced by a closer adherence to the mediterranean diet [41]. Gastrointestinal malignancies and particularly colorectal cancer has been reported more prevalent in patients undergoing coronary angiography for coronary artery disease; the association between the presence of advanced colonic lesions and CVD was stronger in the group with metabolic syndrome and history of smoking [42]. Intermediate phenotypes, such as the metabolic syndrome and diabetes, are increasingly found in close association with both CVD and hormone dependent tumors: evidence is particularly growing for diabetes, as suggested, among others, by a large-scale population-based cohort study in Japan, where, in nearly 100,000 adult subjects, followed up for about 10 years, the total cancer risk was 27% higher in diabetic patients [43]. Reduced insulin sensitivity with compensatory hyperinsulinemia and elevated levels of IGF-1 would stimulate abnormal cell proliferation in different sites [43]. The Moli-sani study On top of the case-control and retrospective studies, a prospective evaluation of the “common soil” hypothesis in an Italian context was badly needed; this prompted us, 6–7 years ago, to plan the Moli-sani project, a randomized prospective cohort study in the Molise region, to investigate gene/environment interactions in the risk of ischemic CVD and tumors. So far, the majority of studies on the identification of risk factors for atherothrombotic disease and malignancies had been conducted in Northern Europe or the USA, with few exceptions for regions of Northern Italy. The Moli-sani project, which aims at recruiting 25,000 adults (older than 35 years, with no upper age limit) randomised from the city-hall registries, has almost completed its cross-sectional phase (24,400 subjects recruited at the end of January 2010)
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and will soon start the follow-up, which includes monitoring not only mortality and morbility for cardiovascular ischemic events and malignant events, but also for those intermediate phenotypes such as diabetes, insulin resistance, obesity, metabolic syndrome which are increasingly considered a predisposing condition for both CVD and hormone-dependent or gastro-intestinal tumors [44]. Moreover, the thorough investigation of life habits and particularly of dietary habits/physical exercise administered to each subject at recruitment, will allow us to correlate the events recorded at follow-up with the most important environmental risk factors for both types of the major killers of our society. Special focus has been addressed to dietary habits through an extremely detailed questionnaire (modified from the EPIC questionnaire to fit with the regional dietary habits) which has already provided useful pieces of information on the degree of adherence to Mediterranean diet of our population and on dietary patterns which correlate with the main risk/protection factors for cardiovascular disease and inflammatory chronic conditions [45,46]. Gene/environment interactions in the determination of disease risk will be evaluated during the follow-up when the appropriate samples collected in the Moli-sani biobank will be used for genetic studies. Indeed, the biological bank of the project will ultimately contain 700,000 biological samples, stored in liquid nitrogen and protected by the most sophisticated technologies (two batches of 14 “paillettes” per subject). Markers related to inflammation and activation of thrombogenesis will be primarily studied as tools to better clarify the link between risk factors of the “common soil”. Conclusions We are confident that the Moli-sani study, with its multiple pieces of information at cross-sectional and with its specific follow-up for both cancer and CVD events, will be well suited to answer the fascinating question whether the “common soil“ hypothesis is more than an hypothesis. Competing interests: The author states she has no conflict of interest in relation to this manuscript. References 1. Donati MB. Cancer and cardiovascular disease: does a common soil exist? Pathophysiol Haemost Thromb 2003;33(suppl 2):1. 2. Donati MB. Thrombosis and cancer: A personal view. Thromb Haemost 2007; 98:126–8. 3. Iacoviello L, Santimone I, Latella MC, de Gaetano G, Donati MB. Nutrigenomics: a case for the common soil between cardiovascular disease and cancer. Genes Nutr 2008;3:19–24. 4. Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS. Atherosclerosis: a cancer of the blood vessels? Am J Clin Pathol 2001;116(Suppl):S97–107. 5. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461–6. 6. Napoleone E, Di Santo A, Camera M, Tremoli E, Lorenzet R. Angiotensinconverting enzyme inhibitors downregulate tissue factor synthesis in monocytes. Circ Res 2000;86:139–43. 7. Di Santo A, Mezzetti A, Napoleone E, et al. Resveratrol and quercetin downregulate tissue factor expression by human stimulated vascular cells. J Thromb Haemost 2003;1:1089–95. 8. Donati MB, Falanga A, Lorenzet R. Cancer and thrombosis: a two way interaction. In: Thrombosis. Fundamental and clinical aspects. Leuven University Press, 2003: pp. 417–31. 9. Napoleone E, Zurlo F, Latella MC, et al. Paclitaxel downregulates tissue factor in cancer and host tumor-associated cells. Eur J Cancer 2009;45:470–7. 10. Napoleone E, Di Santo A, Amore C, et al. Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk? J Thromb Haemost 2007;5:1462–68. 11. Napoleone E, Cutrone A, Zurlo F, et al. Leptin enhances tissue factor synthesis in the human breast cancer cell line MCF7. [abstr. PP-MO-481]. XXII Congress ISTH, 2009, Boston. 12. Gaziano JM. Fifth phase of the epidemiologic transition: the age of obesity and inactivity. JAMA 2010;303:275–6.
13. Jang M, Cai L, Udeani G O, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;275:218–20. 14. Poggi A, Polentarutti N, Donati MB, et al. Blood coagulation changes in mice bearing Lewis lung carcinoma, a metastasizing tumor. Cancer Res 1977;37:272–7. 15. Bani MR, Falanga A, Alessio MG, et al. Blood coagulation changes in nude mice bearing human colon carcinomas. Int J Cancer 1992;50: 75–9. 16. Mussoni L, Poggi A, de Gaetano G, et al. Effect of ditazole, an inhibitor of platelet aggregation, on a metastasizing tumour in mice. Br J Cancer 1978;37:126–9. 17. Poggi A, Mussoni L, Kornblihtt L, et al. Warfarin enantiomers, anticoagulation, and experimental tumor metastasis. Lancet 1978;1: 163–4. 18. Chmielewska J, Poggi A, Janik P, et al. Effect of defibrination with batroxobin on growth and metastasis of JW sarcoma in mice. Eur J Cancer 1980;16:919–23. 19. Donati MB, Poggi A. Malignancy and haemostasis. Br J Haematol 1980;44: 173–82. 20. Poggi A, Donati MB, Garattini S. Fibrin and cancer cell growth: Problems in the evaluation of experimental models. In: Malignancy and the hemostatic system, Raven Press, New York, 1981:pp 89–101. 21. Poggi A, Mussoni L, Kornblihtt L, et al. Warfarin enantiomers, anticoagulation, and experimental tumor metastasis. Lancet 1978;1:163–4. 22. Roncaglioni MC, D’Alessandro AP, Casali B, et al. Gamma-glutamyl carboxylase activity in experimental tumor tissues: a biochemical basis for vitamin K dependence of cancer procoagulant. Haemostasis 1986;16:295–9. 23. Falanga A. The effect of anticoagulant drugs on cancer. J Thromb Haemost 2004; 2:1263–5. 24. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53. 25. Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266–71. 26. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin therapy with dalteparin and survival in advanced cancer: the framing advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004;22:1944–8. 27. Klerk CP, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130–5. 28. Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123–2129. 29. Maugeri N, de Gaetano G, Barbanti M, et al. Prevention of plateletpolymorphonuclear leukocyte interactions: new clues to the antithrombotic properties of parnaparin, a low molecular weight heparins. Haematologica 2005;90:815–21. 30. Maugeri N, Di Fabio G, Barbanti M, et al. Parnaparin, a low molecular weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost 2007;97: 965–73. 31. Elwood PC, Gallagher AM, Duthie GG, et al. Aspirin, salicylates and cancer. Lancet, 2009;373:1301–9. 32. Cuzik J, Otto F, Baron JA, et al. Aspirin and non-stroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 2009; 10:501–7. 33. Holmes MD, Chen WY, Li L, et al. Aspirin intake and survival after breast cancer.2010 J Clin Oncol. published ahead of print February 17. 34. Tunstall-Pedoe H, Kuulasma K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999;353: 1547–57. 35. Trichopoulou D, Lagiou P. Dietary patterns and mortality. Brit J Nutr 2001;85: 133–4 36. La Vecchia C, Chatenoud L, Altieri A, Tavani A. Nutrition and Health: epidemiology of diet, cancer and cardiovascular disease in Italy. Nutr Metab Cardiovasc Dis 2001;11(suppl 4):10–5. 37. Trichopoulou A, Costacou T, Bamia C, Trichopoulou D. Adherence to a mediterranean diet and survival in a greek population. N Engl J Med 2003;348:2599–608. 38. Sofi F, Cesari F, Abbate R et al. Adherence to Mediterranean diet and health status: meta-analysis. Brit Med J 2008;337:1334–41. 39. Fung TT, Hu FB, McCullough ML, et al. Diet quality is associated with the risk of estrogen receptor-negative breast cancer in postmenopausal women. J Nutr 2006;136:466–72. 40. Reedy J, Mitrou PN, Krebs-Smith SM, et al. Index-based dietary patterns and risk of colorectal cancer: the NIH-AARP Diet and Health Study. Am J Epidemiol 2008;168:38–48. 41. Buckland G, Agudo A, Lujan ´ L, et al. Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Am J Clin Nutr 2010;91:381–90. 42. Chan AO, Jim MH, Lam KF, et al. Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA 2007;298: 1412–9.
M.B. Donati / Thrombosis Research 125 (2010) S92–S95 43. Inoue M, Iwasaki M, Otani T, et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 2006 Sep 25;166(17):1871–7. 44. Iacoviello L, Bonanni A, Costanzo S, et al; on behalf of the Moli-sani Project Investigators: The Moli-sani Project, a randomized, prospective cohort study in the Molise region in Italy; design, et al. Ital J Public Health 2007;4:110–8.
S95
45. Centritto F, Iacoviello L, di Giuseppe R, et al; Moli-sani Investigators. Dietary patterns, cardiovascular risk factors and C-reactive protein in a healthy Italian population. Nutr Metab Cardiovasc Dis 2009;19:697–706. 46. di Giuseppe R, Di Castelnuovo A, Centritto F, et al. Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. J Nutr. 2008;138:1939–45.