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Aspirin may modify tumor microenvironment via antiplatelet effect
Medical Hypotheses xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Aspirin may modify tumor microenvironment via antiplatelet effect B.B. Su a,1, J.H. Chen b,1, H. Shi a, Q.Q. Chen a, J. Wan a,⇑ a b
Department of Gastroenterology, South Building, Chinese PLA General Hospital, Beijing 100853, China Department of Medical Oncology, Shenzhen People’s Hospital, Shen Zhen 518020, Guangdong Province, China
a r t i c l e
i n f o
Article history: Received 22 January 2014 Accepted 1 May 2014 Available online xxxx
a b s t r a c t High-quality evidence suggests that aspirin is a promising agent for cancer prevention and treatment. Direct inhibition of cyclooxygenase-2 (COX-2) pathway is generally thought to be the main mechanism by which aspirin inhibits cancer development. However, either pharmacological properties of aspirin or recent results of epidemiologic studies do not support that mechanism. To address this inconsistency, we hypothesize that antiplatelet effect of aspirin via inhibition of COX-1 may be one of potential mechanisms to inhibit carcinogenesis. Aberrant platelet activation will lead to promote hostility of tumor microenvironment by releasing an abundant array of angiogenesis regulators. Given the outstanding ability of antiplatelet, aspirin may restore balance of pro- and anti-angiogenic factors released from platelet to ‘‘normalize’’ tumor vasculature and shape tumor microenvironment to some extent, which will not only diminish tumor aggressiveness and progression, but also enhance the sensitivity to therapeutic treatment. Thus, targeting the platelet activation leading to alter tumor microenvironment may provide a novel way to tumor therapy. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Recently published meta-analyses of results from 5 randomized trials of aspirin treatment to prevent vascular events, have provided evidence that regular use of aspirin before cancer diagnosis had a reduced risk of metastasis and improved survival [1]. Direct inhibition of cyclooxygenase-2 (COX-2) is generally thought to be the key mechanism by which aspirin is contributed to anti-tumor effect [2]. However, regular dose of aspirin only marginally and transiently inhibits COX-2. As known, aspirin inhibits both COX-1 and COX-2; but it preferentially inhibits COX-1. COX-1 gene is highly expressed in platelets where it plays a role in causing platelet activation, via the generation of thromboxane A2 (TXA2) [3]. Because platelets have a limited capacity to generate COX-1 de novo [4], the oral administration of aspirin at low-dose, once daily causes an almost complete suppression of platelet COX-1 which persists throughout dosing interval [5]. On the contrary, aspirin inhibits COX-2 activity in a concentration-dependent fashion [6]. Very high doses of aspirin (>1000 mg), do achieve sufficient ⇑ Corresponding author. Address: Department of Gastroenterology, South Building, Chinese PLA General Hospital, 28# FuXing Road, Beijing 100853, China. Tel.: +86 10 66876246. E-mail address: [email protected] (J. Wan). 1 The first two authors contributed equally to this work.
systemic concentrations to inhibit COX-2 activity [7], and this inhibition can only be maintained in nucleated cells by repeated dosing three or four times daily [8]. In addition, higher dose of aspirin do not further reduce colorectal cancer (CRC) incidence or metastasis, or improve survival [9]. More important, Non-aspirin NSAIDs including selective COX-2 inhibitors are not proved to be more effective than aspirin for survival [10], even have opposite effect [11]. Thus, there must be other mechanism by which aspirin inhibits the development of cancers. It is well documented that tumor cells and tumor microenvironment (TME) maintain complex, bidirectional interactions, which have a deep influence on cancer progression and contribute to almost all of the hallmarks of cancer [12]. Inhibition of tumor cell–microenvironment interactions is emerging as a promising strategy for cancer treatment [13]. A number of previous studies showed that platelets promote cancer initiation, progression, and metastasis [14]. Recently preclinical data have suggested that the crosstalk between tumor cells and TME may be mediated by bioactive factors issued from activated platelets [15]. Thus, targeting platelets may offer a feasible way to block the communication between tumor cells and TME. The antiplatelet effects of aspirin are well established and occur via cyclooxygenase-1 (COX-1) inhibition [16]. It is probably reasonable to assume that aspirin’s utility in tumor prevention and treatment might stems from its ability to target TME by suppressing activation of platelets.
http://dx.doi.org/10.1016/j.mehy.2014.05.007 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007
2
B.B. Su et al. / Medical Hypotheses xxx (2014) xxx–xxx
Tumor microenvironment and platelet It is widely accepted that TME has now emerged as an integral and inseparable part of the carcinogenesis. The crosstalk between tumor cells and TME is complex and bidirectional with involvement of multiple components, including immune cells, endothelial cells, the extracellular matrix. etc. Growing evidence indicated that platelet may also play an important role in TME. The interrelationship between platelets and cancer dates to the 19th century [17]. An increase in platelet number and activity is seen in patients with a wide spectrum of malignancies, which is also correlated with a decrease in overall survival [18]. The leaky tumor vasculature and slowed blood flow facilitate the interaction of platelet with tumor constituents which are capable of inducing platelet activation [19]. Tumor cells also have ability to promote platelet aggregation by releasing thrombosis mediators, such as ADP, tissue factor and thrombin [20]. Enhanced platelet activation has been detected locally within the tumor vascular environment, as well as systemically, as seen in patients with colon, prostrate, breast, lung, or gastric cancer [21]. Activated platelets in turn release a wide range of stored proteins that may mediate the crosstalk between tumor cells and TME, such as a wide range of angiogenic-regulating factors. To date, at least 20 angiogenic-regulating factors have been identified in platelets, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiostatin and insulin-like growth factor (IGF), including both pro-and anti-angiogenic factors [22]. Excess production of pro-angiogenic factors and/or diminished production of anti-angiogenic molecules were considered responsible of tumor vascular abnormality [23]. Abnormal microcirculation in tumors leads to a hostile microenvironment characterized by hypoxia, which render tumor cells highly aggressive and metastatic and resistant to radiotherapy and most conventional chemotherapeutic agents [24]. Restoration of pro-and anti-angiogenic balance in tumors may ‘‘normalize’’ tumor vasculature and thus indirect reduce the hostility of TME [25]. Given an abundant array of positive and negative angiogenesis regulators contained in platelets, platelets may have capacity to stimulate every stage of tumor angiogenesis and to shape TME. In breast cancer patients, Holmes and colleagues demonstrated that aspirin increased serum
and intraplatelet levels of thrombospondin-1, one of the antiangiogenic proteins [26]. Another ex vivo studies in human also have shown that aspirin inhibits thromboxane-mediated release of the sphingosine-1-phosphate (S-1P) from platelets, which is involved in disrupting the endothelial barrier and increase vascular tone at pathophysiological level [27]. Although there is no direct evidence to support aspirin’s effect on normalization of tumor vasculature, it is reasonable to assume that aspirin may regulate the balance of angiogenesis regulators by increasing the antiangiogenic or diminishing pro-angiogenic protein released from platelet (Fig. 1). Hypoxia, one common characteristic of the microenvironment of tumors, through activation of the hypoxia inducible factor (HIF), is at the center of the growth dynamics of tumor cells [28]. Experimental data suggested that HIF is not only activated by hypoxia but also by thrombotic factors [29]. In turn, implantation of platelet into the ischemic hind limbs of rats stimulates angiogenesis by mainly supplying VEGF suggested an important role for hypoxia in platelet activation [30]. However, VEGF often produces vessels that are hyperpermeable and leaky [31], which may aggravate tumor hypoxia. In addition, activated platelets release several mediators, such as PDGF, insulin-like growth factor IGF, which may play a role in the up-regulation of HIF expression [32]. Targeting Platelet-hypoxia crosstalk may be a novel approach to modify TME. From research on the effects of platelet, evidence is accumulating that aspirin may have a role in shaping TME. In fact, more recently a study directly demonstrated that aspirin alter TME in T-cell lymphoma mouse model, which showed that oral administration of aspirin to mice as a prophylactic measure was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumor microenvironment with respect to PH, level of dissolved O2 and glucose [33]. We also once investigated the variability of 18F-fluorodeoxyglucose (18F-FDG) uptake of positron emission tomography (PET), semiquantified as standardized uptake value (SUV), in patients with primary colorectal cancer. There seemed to be a trend of negatively correlation between SUV max and long-term use of aspirin. Since the 18F-FDG uptake was regarded as a possible surrogate for tumor hypoxia [34], from this aspect, it may indicate that aspirin can modulate TME, at least the hypoxia condition.
Fig. 1. Proposed role of aspirin to tumor vasculature normalization by platelet inhibition. (A) Tumor vasculature is structurally and functionally abnormal due to the imbalance of pro-and anti-angiogenic factors. Activated platelet may aggravate this imbalance. (B) Aspirin may restore the balance of pro-and anti-angiogenic factors in tumors by inhibition platelets which contained an abundant array of positive and negative angiogenesis regulators. Restoration of pro- and anti-angiogenic balance in tumors may ‘‘normalize’’ tumor vasculature and thus indirectly reduce the hostility of TME.
Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007
B.B. Su et al. / Medical Hypotheses xxx (2014) xxx–xxx
Hypotheses From a long time, Platelets have long been suspected of having a role in cancer progression and metastasis that has largely been attributed to platelet-mediated enhancement of tumor cell survival, extravasation, and angiogenesis [35]. Further studies show that the multitude of bioactive factors and cytokines released from platelet directly affect tumor cells and TME. Thus, platelet may have some profound effects on tumor microenvironment. Although there are limited data suggesting a direct effect of antiplatelet agents on tumor microenvironment, the finding of aspirin benefit at regular dose in cancer prevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. Our hypothesis is that aspirin may alter tumor microenvironment via platelet inhibition effect by disturbing the crosstalk between tumor cells and TME. Aspirin may restore balance of pro-and anti-angiogenic factors released from platelet so as to ‘‘normalize’’ tumor vasculature and shape tumor microenvironment to some extent, which will not only diminish tumor aggressiveness and progression, but also enhance the sensitivity to therapeutic treatment. Support for this hypothesis would come from identifying architecture and function of tumors vessel changes by aspirin compared to controls and other platelet inhibition agents (e.g. GPIb antibody, clopidogrel) in different tumor models. The metabolic microenvironment changes (e.g. expression of GLUT-1, HIF) would also be evaluated. In clinical, the technology to monitor TME changes should be used to assess tumor vascularity (e.g. DCE MRI, Power Doppler) and oxygenation changes (e.g. PET scanning with hypoxia sensitive tracers) in cancer patients with history of aspirin and other platelet inhibition agents use. Conclusions In the past, the main focus in cancer treatment has been to prevent the promotion and progression of proliferating cancer cells. But in recent years, there have been emerging evidence that warrant the consideration of the TME as a prime target in cancer treatment. Chemotherapy and radiation treatment once were well known for cytotoxic effect, but it is becoming increasingly clear that these forms of treatment can be used to modify the TME [36]. With the development of tumor microenvironment imaging technique, further clinical trials should be designed and conducted to identify the relationship between TME and antiplatelet agent consumption. If this hypothesis is proven to be true, in further designing therapeutic strategies for malignant tumor, antiplatelet drugs should be taken into consideration. Source(s) of funding Supported by a grant from Beijing Municipal Natural Science Foundation (No. 14G30118). Conflict of interest statement None. References [1] Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591–601. [2] Ghosh N, Chaki R, Mandal V, Mandal SC. COX-2 as a target for cancer chemotherapy. Pharmacol Rep 2010;62(2):233–44. [3] Majerus PW. Arachidonate metabolism in vascular disorders. J Clin Invest 1983;72(5):1521–5. [4] Evangelista V, Manarini S, Di Santo A, Capone ML, et al. De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 2006;98(5):593–5.
3
[5] Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982;69(6):1366–72. [6] Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res 2013;191:39–65. [7] Rumble RH, Brooks PM, Roberts MS. Metabolism of salicylate during chronic aspirin therapy. Br J Clin Pharmacol 1980;9(1):41–5. [8] Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9(5):259–67. [9] Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res (Phila) 2012;5(2):164–78. [10] Fuchs CS, Meyerhardt JA, Heseltine DS, et al. Influence of regular aspirin use on survival for patients with stage III colon cancer: findings from Intergroup Trial CALGB 89803. J Clin Oncol 2005;23(16s):3530. [11] Walker AJ, Grainge MJ, Card TR. Aspirin and other non-steroidal antiinflammatory drug use and colorectal cancer survival: a cohort study. Br J Cancer 2012;107(9):1602–7. [12] Fang H, Declerck YA. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res 2013; 73(16):4965–77. [13] Sounni NE, Noel A. Targeting the tumor microenvironment for cancer therapy. Clin Chem 2013;59(1):85–93. [14] Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost 2011;9(2):237–49. [15] Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur J Intern Med 2013;24(5):393–400. [16] Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol 1971;231(25):235–7. [17] Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S. Platelet–tumor–cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer 1973;11(3):704–18. [18] Buergy D, Wenz F, Groden C, Brockmann MA. Tumor–platelet interaction in solid tumors. Int J Cancer 2012;130(12):2747–60. [19] Jurasz P, Alonso-Escolano D, Radomski MW. Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 2004;143(7):819–26 (Epub 2004 Oct 18). [20] Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol 2014;229(8):1005–15. [21] Sierko E, Wojtukiewicz MZ. Inhibition of platelet function: does it offer a chance of better cancer progression control? Semin Thromb Hemost 2007; 33(7):712–21. [22] Radziwon-Balicka A, Moncada de la Rosa C, Jurasz P. Platelet-associated angiogenesis regulating factors: a pharmacological perspective. Can J Physiol Pharmacol 2012;90(6):679–88. [23] Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7(9):987–9. [24] Bar EE, Lin A, Mahairaki V, et al. Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 2010;177(3):1491–502. [25] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307(5706):58–62. [26] Holmes CE, Jasielec J, Levis JE, Skelly J, Muss HB. Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy. Clin Transl Sci 2013;6(5):386–90. [27] Kerage D, Brindley DN, Hemmings DG. Review: novel insights into the regulation of vascular tone by sphingosine 1-phosphate. Placenta 2014;35. Suppl:S86-92. [28] Tsai YP, Wu KJ. Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci 2012;14(19):102. [29] Görlach A, Diebold I, Schini-Kerth VB, et al. Thrombin activates the hypoxiainducible factor-1 signaling pathway in vascular smooth muscle cells: role of the p22(phox)-containing NADPH oxidase. Circ Res 2001;89(1):47–54. [30] Iba O, Matsubara H, Nozawa Y, et al. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation 2002;106(15):2019–25. [31] Sitohy B, Nagy JA, Jaminet SC, Dvorak HF. Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res 2011;71(22):7021–8. [32] Sartori-Cintra AR, Mara CS, Argolo DL, et al. Regulation of hypoxia-inducible factor-1a (HIF-1a) expression by interleukin-1b (IL-1b), insulin-like growth factors I (IGF-I) and II (IGF-II) in human osteoarthritic chondrocytes. Clinics (Sao Paulo) 2012;67(1):35–40. [33] Kumar A, Vishvakarma NK, Tyagi A, Bharti AC, Singh SM. Anti-neoplastic action of aspirin against a T-cell lymphoma involves an alteration in the tumour microenvironment and regulation of tumour cell survival. Biosci Rep 2012; 32(1):91–104. [34] Gu J, Yamamoto H, Fukunaga H, Danno K, et al. Correlation of GLUT-1 overexpression, tumor size, and depth of invasion with18F-2-fluoro-2-deoxyD-glucose uptake by positron emission tomography in colorectal cancer. Dig Dis Sci 2006;51(12):2198–205. [35] Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011;11(2):123–34. [36] Kershaw MH, Devaud C, John LB, Westwood JA, Darcy PK. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology 2013;2(9):e25962.
Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Aspirin may modify tumor microenvironment via antiplatelet effect B.B. Su a,1, J.H. Chen b,1, H. Shi a, Q.Q. Chen a, J. Wan a,⇑ a b
Department of Gastroenterology, South Building, Chinese PLA General Hospital, Beijing 100853, China Department of Medical Oncology, Shenzhen People’s Hospital, Shen Zhen 518020, Guangdong Province, China
a r t i c l e
i n f o
Article history: Received 22 January 2014 Accepted 1 May 2014 Available online xxxx
a b s t r a c t High-quality evidence suggests that aspirin is a promising agent for cancer prevention and treatment. Direct inhibition of cyclooxygenase-2 (COX-2) pathway is generally thought to be the main mechanism by which aspirin inhibits cancer development. However, either pharmacological properties of aspirin or recent results of epidemiologic studies do not support that mechanism. To address this inconsistency, we hypothesize that antiplatelet effect of aspirin via inhibition of COX-1 may be one of potential mechanisms to inhibit carcinogenesis. Aberrant platelet activation will lead to promote hostility of tumor microenvironment by releasing an abundant array of angiogenesis regulators. Given the outstanding ability of antiplatelet, aspirin may restore balance of pro- and anti-angiogenic factors released from platelet to ‘‘normalize’’ tumor vasculature and shape tumor microenvironment to some extent, which will not only diminish tumor aggressiveness and progression, but also enhance the sensitivity to therapeutic treatment. Thus, targeting the platelet activation leading to alter tumor microenvironment may provide a novel way to tumor therapy. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Recently published meta-analyses of results from 5 randomized trials of aspirin treatment to prevent vascular events, have provided evidence that regular use of aspirin before cancer diagnosis had a reduced risk of metastasis and improved survival [1]. Direct inhibition of cyclooxygenase-2 (COX-2) is generally thought to be the key mechanism by which aspirin is contributed to anti-tumor effect [2]. However, regular dose of aspirin only marginally and transiently inhibits COX-2. As known, aspirin inhibits both COX-1 and COX-2; but it preferentially inhibits COX-1. COX-1 gene is highly expressed in platelets where it plays a role in causing platelet activation, via the generation of thromboxane A2 (TXA2) [3]. Because platelets have a limited capacity to generate COX-1 de novo [4], the oral administration of aspirin at low-dose, once daily causes an almost complete suppression of platelet COX-1 which persists throughout dosing interval [5]. On the contrary, aspirin inhibits COX-2 activity in a concentration-dependent fashion [6]. Very high doses of aspirin (>1000 mg), do achieve sufficient ⇑ Corresponding author. Address: Department of Gastroenterology, South Building, Chinese PLA General Hospital, 28# FuXing Road, Beijing 100853, China. Tel.: +86 10 66876246. E-mail address: [email protected] (J. Wan). 1 The first two authors contributed equally to this work.
systemic concentrations to inhibit COX-2 activity [7], and this inhibition can only be maintained in nucleated cells by repeated dosing three or four times daily [8]. In addition, higher dose of aspirin do not further reduce colorectal cancer (CRC) incidence or metastasis, or improve survival [9]. More important, Non-aspirin NSAIDs including selective COX-2 inhibitors are not proved to be more effective than aspirin for survival [10], even have opposite effect [11]. Thus, there must be other mechanism by which aspirin inhibits the development of cancers. It is well documented that tumor cells and tumor microenvironment (TME) maintain complex, bidirectional interactions, which have a deep influence on cancer progression and contribute to almost all of the hallmarks of cancer [12]. Inhibition of tumor cell–microenvironment interactions is emerging as a promising strategy for cancer treatment [13]. A number of previous studies showed that platelets promote cancer initiation, progression, and metastasis [14]. Recently preclinical data have suggested that the crosstalk between tumor cells and TME may be mediated by bioactive factors issued from activated platelets [15]. Thus, targeting platelets may offer a feasible way to block the communication between tumor cells and TME. The antiplatelet effects of aspirin are well established and occur via cyclooxygenase-1 (COX-1) inhibition [16]. It is probably reasonable to assume that aspirin’s utility in tumor prevention and treatment might stems from its ability to target TME by suppressing activation of platelets.
http://dx.doi.org/10.1016/j.mehy.2014.05.007 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007
2
B.B. Su et al. / Medical Hypotheses xxx (2014) xxx–xxx
Tumor microenvironment and platelet It is widely accepted that TME has now emerged as an integral and inseparable part of the carcinogenesis. The crosstalk between tumor cells and TME is complex and bidirectional with involvement of multiple components, including immune cells, endothelial cells, the extracellular matrix. etc. Growing evidence indicated that platelet may also play an important role in TME. The interrelationship between platelets and cancer dates to the 19th century [17]. An increase in platelet number and activity is seen in patients with a wide spectrum of malignancies, which is also correlated with a decrease in overall survival [18]. The leaky tumor vasculature and slowed blood flow facilitate the interaction of platelet with tumor constituents which are capable of inducing platelet activation [19]. Tumor cells also have ability to promote platelet aggregation by releasing thrombosis mediators, such as ADP, tissue factor and thrombin [20]. Enhanced platelet activation has been detected locally within the tumor vascular environment, as well as systemically, as seen in patients with colon, prostrate, breast, lung, or gastric cancer [21]. Activated platelets in turn release a wide range of stored proteins that may mediate the crosstalk between tumor cells and TME, such as a wide range of angiogenic-regulating factors. To date, at least 20 angiogenic-regulating factors have been identified in platelets, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiostatin and insulin-like growth factor (IGF), including both pro-and anti-angiogenic factors [22]. Excess production of pro-angiogenic factors and/or diminished production of anti-angiogenic molecules were considered responsible of tumor vascular abnormality [23]. Abnormal microcirculation in tumors leads to a hostile microenvironment characterized by hypoxia, which render tumor cells highly aggressive and metastatic and resistant to radiotherapy and most conventional chemotherapeutic agents [24]. Restoration of pro-and anti-angiogenic balance in tumors may ‘‘normalize’’ tumor vasculature and thus indirect reduce the hostility of TME [25]. Given an abundant array of positive and negative angiogenesis regulators contained in platelets, platelets may have capacity to stimulate every stage of tumor angiogenesis and to shape TME. In breast cancer patients, Holmes and colleagues demonstrated that aspirin increased serum
and intraplatelet levels of thrombospondin-1, one of the antiangiogenic proteins [26]. Another ex vivo studies in human also have shown that aspirin inhibits thromboxane-mediated release of the sphingosine-1-phosphate (S-1P) from platelets, which is involved in disrupting the endothelial barrier and increase vascular tone at pathophysiological level [27]. Although there is no direct evidence to support aspirin’s effect on normalization of tumor vasculature, it is reasonable to assume that aspirin may regulate the balance of angiogenesis regulators by increasing the antiangiogenic or diminishing pro-angiogenic protein released from platelet (Fig. 1). Hypoxia, one common characteristic of the microenvironment of tumors, through activation of the hypoxia inducible factor (HIF), is at the center of the growth dynamics of tumor cells [28]. Experimental data suggested that HIF is not only activated by hypoxia but also by thrombotic factors [29]. In turn, implantation of platelet into the ischemic hind limbs of rats stimulates angiogenesis by mainly supplying VEGF suggested an important role for hypoxia in platelet activation [30]. However, VEGF often produces vessels that are hyperpermeable and leaky [31], which may aggravate tumor hypoxia. In addition, activated platelets release several mediators, such as PDGF, insulin-like growth factor IGF, which may play a role in the up-regulation of HIF expression [32]. Targeting Platelet-hypoxia crosstalk may be a novel approach to modify TME. From research on the effects of platelet, evidence is accumulating that aspirin may have a role in shaping TME. In fact, more recently a study directly demonstrated that aspirin alter TME in T-cell lymphoma mouse model, which showed that oral administration of aspirin to mice as a prophylactic measure was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumor microenvironment with respect to PH, level of dissolved O2 and glucose [33]. We also once investigated the variability of 18F-fluorodeoxyglucose (18F-FDG) uptake of positron emission tomography (PET), semiquantified as standardized uptake value (SUV), in patients with primary colorectal cancer. There seemed to be a trend of negatively correlation between SUV max and long-term use of aspirin. Since the 18F-FDG uptake was regarded as a possible surrogate for tumor hypoxia [34], from this aspect, it may indicate that aspirin can modulate TME, at least the hypoxia condition.
Fig. 1. Proposed role of aspirin to tumor vasculature normalization by platelet inhibition. (A) Tumor vasculature is structurally and functionally abnormal due to the imbalance of pro-and anti-angiogenic factors. Activated platelet may aggravate this imbalance. (B) Aspirin may restore the balance of pro-and anti-angiogenic factors in tumors by inhibition platelets which contained an abundant array of positive and negative angiogenesis regulators. Restoration of pro- and anti-angiogenic balance in tumors may ‘‘normalize’’ tumor vasculature and thus indirectly reduce the hostility of TME.
Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007
B.B. Su et al. / Medical Hypotheses xxx (2014) xxx–xxx
Hypotheses From a long time, Platelets have long been suspected of having a role in cancer progression and metastasis that has largely been attributed to platelet-mediated enhancement of tumor cell survival, extravasation, and angiogenesis [35]. Further studies show that the multitude of bioactive factors and cytokines released from platelet directly affect tumor cells and TME. Thus, platelet may have some profound effects on tumor microenvironment. Although there are limited data suggesting a direct effect of antiplatelet agents on tumor microenvironment, the finding of aspirin benefit at regular dose in cancer prevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. Our hypothesis is that aspirin may alter tumor microenvironment via platelet inhibition effect by disturbing the crosstalk between tumor cells and TME. Aspirin may restore balance of pro-and anti-angiogenic factors released from platelet so as to ‘‘normalize’’ tumor vasculature and shape tumor microenvironment to some extent, which will not only diminish tumor aggressiveness and progression, but also enhance the sensitivity to therapeutic treatment. Support for this hypothesis would come from identifying architecture and function of tumors vessel changes by aspirin compared to controls and other platelet inhibition agents (e.g. GPIb antibody, clopidogrel) in different tumor models. The metabolic microenvironment changes (e.g. expression of GLUT-1, HIF) would also be evaluated. In clinical, the technology to monitor TME changes should be used to assess tumor vascularity (e.g. DCE MRI, Power Doppler) and oxygenation changes (e.g. PET scanning with hypoxia sensitive tracers) in cancer patients with history of aspirin and other platelet inhibition agents use. Conclusions In the past, the main focus in cancer treatment has been to prevent the promotion and progression of proliferating cancer cells. But in recent years, there have been emerging evidence that warrant the consideration of the TME as a prime target in cancer treatment. Chemotherapy and radiation treatment once were well known for cytotoxic effect, but it is becoming increasingly clear that these forms of treatment can be used to modify the TME [36]. With the development of tumor microenvironment imaging technique, further clinical trials should be designed and conducted to identify the relationship between TME and antiplatelet agent consumption. If this hypothesis is proven to be true, in further designing therapeutic strategies for malignant tumor, antiplatelet drugs should be taken into consideration. Source(s) of funding Supported by a grant from Beijing Municipal Natural Science Foundation (No. 14G30118). Conflict of interest statement None. References [1] Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591–601. [2] Ghosh N, Chaki R, Mandal V, Mandal SC. COX-2 as a target for cancer chemotherapy. Pharmacol Rep 2010;62(2):233–44. [3] Majerus PW. Arachidonate metabolism in vascular disorders. J Clin Invest 1983;72(5):1521–5. [4] Evangelista V, Manarini S, Di Santo A, Capone ML, et al. De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 2006;98(5):593–5.
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[5] Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982;69(6):1366–72. [6] Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res 2013;191:39–65. [7] Rumble RH, Brooks PM, Roberts MS. Metabolism of salicylate during chronic aspirin therapy. Br J Clin Pharmacol 1980;9(1):41–5. [8] Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9(5):259–67. [9] Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res (Phila) 2012;5(2):164–78. [10] Fuchs CS, Meyerhardt JA, Heseltine DS, et al. Influence of regular aspirin use on survival for patients with stage III colon cancer: findings from Intergroup Trial CALGB 89803. J Clin Oncol 2005;23(16s):3530. [11] Walker AJ, Grainge MJ, Card TR. 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Please cite this article in press as: Su BB et al. Aspirin may modify tumor microenvironment via antiplatelet effect. Med Hypotheses (2014), http:// dx.doi.org/10.1016/j.mehy.2014.05.007