It is widely recognized that inflammation may trigger cancer initiation and progression [
66‐
69]. Arachidonic acid is metabolized enzymatically
via COX and LOX generating bioactive lipids termed eicosanoids: 2-series prostaglandins (PGs) and thromboxanes (Txs) (COX pathway) or 4-series leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) (LOX pathway) [
70‐
72]. Tumor cell-platelet interaction may activate COX individually or COX and LOX in concert resulting in production of the above mentioned eicosanoids. These in turn are involved in the growth and progression of cancers by regulating such processes as apoptosis, angiogenesis, and tumor cell invasiveness [
68‐
73]. Thrombin-activated platelets (activation dependent on PARs) are a source of 12- and 15-HETE, as well as TxA2 [
2,
74,
75]. The release of TxA2 into the microenvironment activates prostanoid receptors (TP) on platelets resulting in increased expression of GPIIb/IIIa (integrin αIIbβ3) and platelet aggregation. Preincubation of platelet-rich plasma with TxA2 receptor inhibitor SQ-29,548 decreased platelet aggregation induced by tumor osteogenic sarcoma cells without affecting TxA2 release [
76]. TCIPA in carcinosarcoma cells resulted in 12-HETE activation and a subsequent increase in platelet expression of GPIIb/IIIa [
77].
3.1.1 Cyclooxygenase inhibitors
Compelling evidence exists for antitumor activity of the COX-1 and -2 inhibitor, aspirin, which disrupts platelet function by inhibiting prostaglandin and thromboxane formation [
78‐
80]. Expression of COX-1 and/or COX-2 is cell-dependent. ECs and tumor cells express COX-2, but platelets express COX-1 [
11]. It is difficult to distinguish which effects observed in experimental studies are attributable to which isoform of the enzyme, and the exact anticancer mechanisms of aspirin remain unexplained. There were hypotheses that aspirin benefits from COX-2 inhibition were from its antiproliferative and proapoptosis potential. However, it has been argued that aspirin at low doses could not result in the blood concentrations necessary to impact those processes [
17]. Thus, the hypothesis that a dominant mechanism for the cancer preventive and anti-metastasis property of aspirin is associated with its antiplatelet activity (COX-1 inhibition) is plausible [
78]. Platelets have been proven to impact metastases by direct and indirect interactions with tumor cells [
1‐
3]. As aspirin can induce platelet apoptosis
via caspase-3 activation [
81], its cancer preventive role may be explained by thus interfering with platelet-induced epigenetic modifications of tumor cells during early phases of colorectal tumorigenesis, for example. Platelet activation in intestine may lead to local inflammation and cellular transformation [
82].
Experiments with cancer cell lines
in vitro provided proof that the anticancer effect of aspirin is associated with its influence on cross-talk between platelets and cancer cells (Table
1). Incubation of HT29 human colon carcinoma cells with human platelets induced their transformation from epithelial to mesenchymal-like features of cancer cells that is an indispensable step for cancer dissemination [
3,
13]. Enhanced cancer cell mobility was the result of E-cadherin downregulation and Twist1 upregulation. There was also a proaggregatory effect on the platelets by the cancer cells. Similar results have been described for ovarian cancer cell line SK-OV-3, where platelets increased their invasive potential by inducing the epithelial-to-mesenchymal transition phenotype [
85], but that could be inhibited by aspirin. The anticancer potential of aspirin when administered in low, antiplatelet doses to colon and pancreatic cancer cells was associated with inhibition of oncoprotein c-MYC expression and a reduction in proliferative potential of cancer cells [
19].
Table 1
Aspirin role in cancer prevention and treatment—in vitro and in vivo studies
| Platelet apoptosis via caspase-3 activation |
Ding 2014 [ 83] and Ding 2017 [ 84] MM1.S and RPMI-8226 myeloma cell lines | Activation of caspases, upregulation of Bax, and downregulation of Bcl-2 and VEGF Potentiation of inhibitory effect of bortezomib |
Cook 2015 [ 85] SK-OV-3 ovarian cancer cells | Inhibition of epithelial-to-mesenchymal transition phenotype |
Mitrugno 2017 [ 19] SW480 colon and PANC-1 cancer cells | Inhibition of oncoprotein c-MYC expression and reduced proliferative potential of cancer cells |
Vad 2014 [ 86] B16-F0 melanoma cells and skin B16-F0 melanoma tumor mouse model | Increase in reactive oxygen species (ROS) formation, Inhibition of tumor growth |
Guillem-Llobat 2016 [ 18] HT29 human colon carcinoma cells | Inhibition of epithelial-to-mesenchymal transition phenotype reduced metastases rate |
Sitia 2014 [ 87] Hepatocellular carcinoma | Reduction of immune-mediated pathological effects in the liver and tumorigenesis |
Ogawa 2014 [ 66] Lewis lung carcinoma cells in mice model | Reduction of mediastinal lymph node metastasis |
| Inhibition of pro-angiogenic activity of the platelets |
He 2017 [ 89] PC-3 prostate cancer cells | Induction of apoptosis by strong inhibition of NF-κB and decreases in the levels of phospho-Stat3 and phospho-Erk1/2 |
The injection of platelet-exposed HT29 cells into the tail vein of humanized, immunodeficient mice resulted in higher incidence of lung metastasis. Inhibition of platelet COX-1 by aspirin prevented the
in vitro changes as well as reduced the metastatic rate
in vivo [
1,
17]. The inhibitory effect of aspirin was also observed on B16-F0 melanoma cell proliferation and tumor growth in a mouse model [
86].
Preclinical experiments also demonstrated the vital role of platelet activation in pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) as well as the anticancer effectiveness of dual platelet inhibitors (aspirin plus clopidogrel) [
87,
90]. Platelet activation in HBV-HCC mouse models led to accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells in the liver, increased hepatocellular proliferation, liver fibrosis, and hepatocarcinogenesis. Platelet inhibition prevented injury of liver cells and tumor development most likely due to the reduction of immune-mediated pathological effects in the liver.
Aspirin has also been shown to reduce mediastinal lymph node metastasis in a mouse model after injection of LLC cells [
66]. Aspirin had no effect on primary tumor in the lung but significantly reduced mouse mortality. There is heterogeneity in the human response to aspirin in the setting of lung cancer. An English study found no survival benefit [
91], while a German study suggested that there are benefits to specific subgroups that warrant careful scrutiny [
92].
Aspirin is also an important antiangiogenic agent [
88]. Human platelets activated with thrombin secrete both VEGF and endostatin, ultimately promoting tubule-like formation and increased proliferation of endothelial cells. Surprisingly, these proangiogenic actions were only slightly suppressed by VEGF receptor-neutralizing antibody. The other platelet-induced signaling inhibitors of protein kinase C (PKC), p38, ERK1/2, Src kinases, or PI3K/Akt also exerted only partial inhibitory effects. In contrast, aspirin fully blocked the pro-angiogenic activity of the platelet releasate.
A novel derivative of aspirin, nitric oxide- and hydrogen sulfide-releasing hybrid or NOSH-aspirin (NBS-1120), has been developed that is stronger than classic aspirin in its potential to inhibit tumor growth and decrease tumor size [
28]. Moreover, it is suggested that aspirin does not prevent TCIPA while the aspirin prodrug, 5-nicotinate salicylate (ST0702 salicylate), is effective in TCIPA inhibition [
93].
Another inhibitor of platelet COX and PDGF, trapidil, does prevent spontaneous pulmonary metastases formation in mice, but only when administered after excision of the primary tumor [
94]. Non-steroidal anti-inflammatory drugs, e.g., flurbiprofen, prostacyclin analogues, and thromboxane A2 synthase inhibitors, also significantly decrease spontaneous metastases formation [
95,
96].
An antagonist of the prostaglandin(PG)E2 EP3 receptor, DG-041, prevented induction of mesenchymal-like changes in colon cancer cells by lowering E-cadherin expression and elevating Twist1 protein resulting in disrupted metastatic potential. Cancer cell motility and proaggregatory action on platelets were also abrogated by this drug [
18].
Solid-phase von Willebrand Factor (sVWF) is known to mediate TCIPA. Unstimulated platelets can adhere irreversibly to sVWF and stimulation by ADP, thrombin, or ristocetin increases adherence [
97]. However, aggregation can be blocked by S-nitroso-glutathione (GSNO) and prostacyclin (PGI(2)). Moreover, pre-incubation of platelets with PGI(2) inhibits sVWF-tumor cell-stimulated platelet surface expression of GPIIb/IIIa essential for tumor cell/platelet interactions [
98].
The majority of clinical data relates to aspirin use in colorectal cancer (CRC) which is well recognized to be associated with inflammation (colitis–dysplasia–carcinoma) [
78]. Although the Physicians’ Health Study reported in 1998 that they found no association between the use of aspirin and the incidence of CRC [
99], subsequent studies reported more promising results [
24,
100]. Long-term effects of aspirin on CRC incidence and mortality during the more than 20-year follow-up were presented in the analysis of their randomized trials [
24,
100]. Aspirin taken daily for 5 years or longer at a minimal dose of 75 mg reduced both incidence and mortality due to CRC with the greatest preventive effect for cancers of the proximal colon. Importantly, aspirin reduced the incidence of CRC and benign polyps (adenomas) in the general population and individuals with a history of adenomas or CRC [
100,
101]. In the general population, the CRC incidence was decreased by 26% (RR 0.74, 95% CI 0.57 to 0.97), while in patients with a history of adenomas or CRC, risk of adenoma recurrence was reduced by 21% [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92]. In case-control studies, regular use of aspirin has also been documented to reduce risk of CRC in good agreement with results of the randomized trials [
102].
The preventive role of aspirin has now been documented in multiple studies of other cancers [
78,
103].
The assessment of short-term effects of aspirin from the analyses of 51 randomized controlled trials that were designed to evaluate the role of aspirin in the primary and secondary prevention of vascular events demonstrated that aspirin reduced the incidence of several cancers from 3 years onwards [
104]. In addition to having a preventive role in cancer, depending on the duration of treatment, aspirin also improves the results of treatment among cancer patients [
7,
17,
24].
Pooled data for eight randomized controlled trials demonstrated that daily aspirin reduced deaths due to cancer (OR 0.79, 95% CI 0.68 to 0.92) [
24]. A 5 years follow-up (data assessed in seven trials) revealed a significant benefit from daily aspirin for all cancers (HR 0.66, 95% CI 0.50 to 0.87) with the best results observed for gastrointestinal cancers (HR 0.46, 95% CI 0.27 to 0.77). Interestingly, three trials that assessed the 20-year risk of cancer death also showed that patients who took aspirin had a lower risk of cancer-associated death (HR 0.78, 95% CI 0.70 to 0.87 and for gastrointestinal cancers HR 0.65, 95% CI 0.54 to 0.78). Taking into consideration all solid cancers, the benefits significantly increased with treatment duration of 7.5 years and longer. The subgroup analysis indicated that for esophageal, pancreatic, brain, and lung cancers, this time may be around 5 years. Another important conclusion by authors was that the effects of aspirin did not depend on dose (75 mg and over 75 mg) and did not differ in relation to gender and smoking status. The final result was that the absolute reduction in 20-year risk of cancer death was 7.08% (95% CI 2.42 to 11.74) in patients 65 years or older at randomization. The decreased risk of death among patients diagnosed with cancer during trials may have resulted from the lower frequency of distant metastases observed in the aspirin group
versus control [
105], particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11–0·57,
p = 0·0008). Aspirin lessened the frequency of metastasis both at initial diagnosis and during follow-up in patients who did not present with metastasis initially.
At this point, data regarding breast cancer are inconclusive [
17,
106]. A 10-year Women’s Health Study Trial with almost 40,000 women did not correlate aspirin use with decreased breast cancer incidence [
26], while other meta-analyses have demonstrated less development of breast cancer (9–30%) among women who have been taking aspirin [
107,
108]. The differences in results may be associated with the length of time aspirin is taken [
17] Shiao]. A prospective observational study of 4164 women with breast cancer showed that decreased risk of distant recurrence and breast cancer death is observed when aspirin is taken at least 12 months [
7]. The newest retrospective analysis of 222 stage II and III triple-negative breast cancer (TNBC) patients demonstrates improvement in 5-year DFS (80.1
vs 62.6%,
p = 0.04) and 5-year DMR (9.0
vs 31.6%,
p = 0.007) in the aspirin group compared with the control group. Intriguingly, aspirin also decreased the rate of central nervous system (CNS) metastases.
The benefits of an aspirin regimen were also documented for lowering prostate cancer incidence [
109‐
112] and for prostate cancer patients, especially in the high-risk group [
4,
113]. The study, comprising nearly 6000 patients after prostatectomy or radiotherapy who received different anticoagulants (AC), showed that aspirin use was associated with lower prostate cancer-specific mortality (PCSM) compared with the non-AC group (adjusted hazard ratio 0.43; 95% CI 0.21 to 0.87;
P = 0.02) [
4]. Disease recurrence and bone metastasis were also significantly lower in the AC group.
The prevention of carcinogenesis in cell line models and improvement of recurrence-free survival and overall survival (52.8
vs 47.9%;
p = 0.021 and 80.3
vs 65.4%;
p < 0.001, respectively) were observed among HBV-related hepatocellular carcinoma (HCC) patients after liver resection [
20].
Aspirin assessment in cancer patients summarizes Table
2.
Table 2
Aspirin assessment in cancer patients
Colorectal (CRC) | Analysis of randomized trials Analysis of randomized trials | Aspirin taken daily for 5 years and longer at the dose of at least 75 mg reduced both incidence and mortality due to CRC. Decreased risk of adenomas in CRC patients. |
Prostate cancer |
n = 6000 A multi-institutional registry | Lower prostate cancer-specific mortality (3 v 8%). Increased risk of upper gastrointestinal bleeding |
Hepatocellular carcinoma | Retrospective analysis, n = 442 | Improvement of recurrence-free survival and overall survival, reduced the risk of HCC recurrence and overall mortality |
Breast cancer | Prospective observational study,
n = 4164 | Decreased risk of distant recurrence and breast cancer death |
Gastrointestinal, esophageal, pancreatic, brain, and lung cancers | Analysis of eight randomized trials | Reduced deaths due to cancer |
The recommendations on the preventive use of aspirin are summarized on the official website of the US preventive services task force (Table
3).
Table 3
Recommendations on the preventive use of aspirin of the US preventive services task force
Adults aged 50 to 59 years with a ≥10% 10-year CVD risk | Initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC) in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. |
Adults aged 60 to 69 years with a ≥10% 10-year CVD risk | The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin. |
Adults younger than 50 years | The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than 50 years. |
Adults aged 70 years or older | The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults aged 70 years or older. |