Aspirin hinders hypoxia-mediated effects that promote the growth of non-small cell lung cancer (NSCLC), according to the results of a recent study in Pathology – Research and Practice.
“Epidemiological and clinical studies have illustrated that regular aspirin consumption decreases the risk of NSCLC, which indicates that aspirin could be a promising agent in the treatment of this cancer,” wrote corresponding author Dr. Senming Wang, Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, and colleagues.
One common aspect of the microenvironment of solid tumor cells is hypoxia, which results from the rapid expansion of tumor cells and their intricate vasculature. Hypoxia is also linked to more aggressive tumor properties, resistance to therapies, and worsened clinical outcomes.
Hypoxia up-regulates the expression of hypoxia-inducible factor-1α (HIF-1α), which then regulates different biological signals, including stem cell markers. Hypoxia is known to promote drug resistance and cancer cell “stemness” (the ability to self-renew and differentiate into different tumor cell types) in lung cancer.
The hypoxic induction of gene expression in solid tumors occurs via HIF-1α accumulation. The accumulation of HIF-1α triggers the transcription of COX-2 in A549 NSCLC cells under hypoxic conditions. In turn, the activation of the COX-2/PGE2 pathway plays a big role in the survival of cancer cells and the angiogenesis of tumors. Of note, COX-2 is often overexpressed in NSCLC and predicts a worsened prognosis.
The researchers hypothesized that the COX-2/PGE2 pathway was an important pathway in NSCLC therapy. So, they targeted it with aspirin, which is a nonselective COX inhibitor.
Although poorly understood, direct inhibition of COX-2 is generally accepted as the main pathway by which aspirin inhibits cancer development.
“As expected, aspirin inhibited tumorigenesis and stemness under hypoxic conditions via HIF-1α/COX-2/PGE2 signaling in NSCLC cells,” they wrote.
Importantly, the results of the current study concur with those of another study in which investigators found that COX-2 maintains the stemness of nasopharyngeal carcinoma cell lines.
Aspirin vs exosomes
Dr. Wang and colleagues also noted that cancer cells may communicate and boost tumorigenesis by using exosomes.
To test this, they performed protein estimation in the tumor microenvironment, along with an exosome quantification assay, and found that hypoxia significantly increased exosome protein levels and numbers in a conditioned media. Hypoxia also boosted HIF-1α and COX-protein levels.
The investigators also found that the synergistic effect of aspirin and cisplatin on lung cancer cells could be due to functional exosome changes. These results are similar to those found in another study in which researchers demonstrated that hypoxia triggers the release of exosomes in breast cancer, which may be controlled by HIF-1α.
Exosomes are small vesicles with diameters between 30 nm and 100 nm. They house microRNAs, mRNAs, proteins, and DNA fragments. In one recent study, experts suggested that exosomes secreted under hypoxia boost the invasiveness and stemness of cancer cells, as well as initiate tumor microenvironment recruitment and reprogramming in prostate cancer.
“We provide evidence of the inhibitory effect of aspirin on the stemness of human lung cancer cells and demonstrate that aspirin impedes the exosome secretion and malignant paracrine effect of these cells,” the researchers concluded.
In summary, the authors showed that aspirin has therapeutic uses for hindering the development and stemness of lung cancer.