Endogenous modulators in lung cancer

Abstract

This editorial aimed to consolidate current evidence on the role of major endogenous modulators—nitric oxide (NO), prostaglandins (PGs), thromboxanes (TXs), and endothelins (ETs) in the lung carcinogenesis, their receptor-specific actions, compensatory feedback mechanisms, and their role in tumor immune evasion and angiogenesis. We searched PubMed and Google Scholar with free-text and MeSH combinations of terms including "lung cancer", "nitric oxide", "inducible NOS", "COX-2", "prostaglandin E₂", "thromboxane A₂", "endothelin", "angiogenesis", and "immunosuppression". We examined English-language publications for mechanistic data, preclinical models, and clinical correlates, and synthesized findings from both animal and human tissue studies. We highlight here the dual, concentration-dependent actions of NO, PG-E2's immunosuppressive and pro-angiogenic actions via E-Prostanoid (EP2/EP4) receptors, thromboxane A₂'s pro-metastatic functions by thromboxane receptor signaling and interaction with platelet-tumor interaction, and the underappreciated roles of ETs. We also point to gaps in the existing literature on the differential roles of other prostanoid subtypes (e.g., PGI2, PGD2), hypoxia-inducible factor-1α's role in regulation of inflammatory cascades, and clinical significance of compensatory upregulation of TX synthase following cycloxygenase-2 inhibition. These observations underscore the potential need for receptor-targeted therapies, biomarker-guided patient stratification, and improved translational models to inform the development of personalized anti-inflammatory interventions in lung cancer.

Key Words: Lung cancer; Nitric oxide; Prostaglandins; Thromboxanes; Tumor microenvironment; Angiogenesis; Biomarkers; Cyclooxygenase

Core Tip: Endogenous mediators—nitric oxide, prostaglandin E₂, thromboxane A₂, and endothelins—induce lung tumor angiogenesis, immune escape, and metastasis through crosstalk signaling loops; targeting their individual receptors and employing eicosanoid biomarker profiles for patient stratification could enable more effective, patient-specific anti-inflammatory therapies in lung cancer.

TO THE EDITOR

Lung cancer is the most common cause of death all over the world, accounting for 2.5 million new cases and 1.8 million deaths in 2022[1]. It is the most common cause of incidence and death among men and causes almost one out of every five cancer deaths worldwide[1]. According to a study by Jemal et al[2], there is a greater incidence of lung cancer among young women compared to young men. The etiological risk factors for lung cancer include tobacco smoking, unhealthy diet, occupational and air pollution exposures, with tobacco use being the major etiological factor in lung carcinogenesis[3]. The five-year survival for lung and bronchus cancer overall is approximately 28% despite the advent of targeted therapy and immune checkpoint inhibitors[4].

The two primary classes of lung cancer are: Small cell lung cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC)[5]. NSCLC comprises the subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma[5]. In this editorial, we discuss the research by Demirel and Sinag[6] on the role of nitric oxide, prostaglandins, thromboxanes, and endothelins in lung cancer.

ROLES OF ENDOGENOUS MODULATORS IN LUNG CARCINOGENESIS

Demirel and Sinag[6] identify the four principal endogenous modulators—nitric oxide (NO), prostaglandins (PGs), Thromboxanes (TXs), and endothelins (ETs) —regulating the lung tumor microenvironment. Each is synthesized by well-defined enzymatic cascades: NO via NOS (nitric oxide synthases), eNOS (endothelial NOS), nNOS (neuronal NOS), and iNOS (inducible NOS); PGs and TXs from arachidonic acid by cyclooxygenases-1/2 (COX1/2) and downstream prostaglandin or thromboxane synthases; and ETs through endothelinconverting enzymes on preproendothelin peptides[7-9]. Their overall actions regulate angiogenesis, immune tone, and metastatic potential.

Role of NO in lung carcinogenesis

NO production in tumors comes mainly from iNOS induction due to inflammatory cytokines (e.g., Interferon-γ, Tumor necrosis factor-α), while eNOS produces basal NO in endothelial cells[7]. Demirel and Sinag[6] explain NO's biphasic function: Low eNOS-derived NO suppresses endothelial proliferation through cyclic guanosine monophosphate signaling, and high iNOS-derived NO generates reactive oxygen species that kill DNA and induce angiogenesis. They cite Zhang et al[10], who demonstrated in murine models of NSCLC that iNOS knockout resulted in decreased microvessel density. However, they do not provide information about human research that has demonstrated tumor-associated macrophages are a dominant source of NO in NSCLC and that macrophage-derived NO is associated with immunosuppressive M2 phenotypes[11]. In addition, nNOS role in lung epithelial cells—a possible site for localized NO bursts, also influences early carcinogenesis[7]. One study has also examined the clinical data and found the association of elevated circulating nitrate concentration with poor survival in lung cancer patients[12].

Role of prostaglandins in lung carcinogenesis

Prostaglandins are formed when COX-2 converts arachidonic acid to Prostaglandin H2 (PGH2), which is then converted to PGE2 by PGE synthase[8]. Demirel and Sinag[6] correctly state that PGE2-(E-Prostanoid) EP2/EP4 signaling inhibits CD8+ cytotoxic T-cell function and induces regulatory T-cell expansion, referencing Li et al’s research in NSCLC tissues[13]. They also point out the overexpression of COX-2 in premalignant lesions. However, their manuscript lacked information on the differential functions of other PGs—PGD2 and PGI2—in tumor biology. PGI2, for instance, can regulate endothelial integrity and trafficking of immune cells, and has been associated with low levels and poor prognosis[14]. There are preclinical models employing non-physiological COX inhibitors at supra-therapeutic doses, which might not be representative of accessible patient exposures[15]. A better balance would result from addressing EP receptor subtype-specific effects and incorporating clinical trials of COX-2 inhibitors in NSCLC[16].

Role of thromboxanes in lung carcinogenesis

Thromboxane A2 (TXA2) is formed when cyclooxygenase-1/2 (COX-1/2) converts arachidonic acid into PGH2, which is then converted into TXA2 by thromboxane synthase[8]. Demirel and Sinag[6] mention that high levels of TXA2 were associated with unfavourable prognosis in NSCLC and provide evidence that TXA2 promotes platelet-tumor cell aggregation, shielding tumor cells against shear-induced damage and immune elimination. There is newer evidence regarding the thromboxane receptor (TP) on tumor cells themselves; activation of TP can induce cancer cell growth and migration regardless of platelet interaction[17]. Compensatory upregulation of thromboxane synthase after COX-2 inhibition has also been seen in NSCLC patient specimens, suggesting a possible mechanism of resistance to COX-targeted therapies[18]. Moreover, most preclinical metastasis models referenced utilize murine models with mouse platelets, which are quite different from human platelets, thereby precluding extrapolation to the clinic.

Role of endothelins in lung carcinogenesis

Endothelin-1 (ET-1) is synthesized when endothelin-converting enzymes-1/2 cleave prepro-endothelin peptides into the active 21-amino-acid peptide[9]. Demirel and Sinag[6] have indicated that high levels of ET-1 and overexpression of the endothelin type-A (ETA) receptor in NSCLC samples correlate with higher microvessel density and worse overall survival[19]. ETA activation is implicated in the activation of MAPK and PI3K/Akt (mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B) cascades, leading to tumor cell growth and apoptosis resistance, while endothelin type-B receptor signaling may lead to the release of endothelial nitric oxide and increased vascular permeability, thus promoting tumor cell intravasation and metastasis[20,21]. Compensatory upregulation of components of endothelin pathways upon COX-2 inhibition is also emerging evidence, suggesting functional redundancy with prostanoid networks and putative mechanisms of resistance to anti-inflammatory treatments[22]. Most mechanistic information, however, arises from in vitro cell-line experiments or murine xenograft models that do not have the complete human stromal-immune microenvironment, which restricts direct clinical application[23].

Pathway interdependence in lung carcinogenesis

Demirel and Sinag[6] have described a COX-2 → PGE2 → iNOS/TX synthase loop wherein COX-2-derived PGE2 acts on EP receptors to upregulate inducible NOS and thromboxane synthase, amplifying reactive nitrogen species production, prostanoid signaling, and downstream angiogenesis. Systems-biology analyses confirm this model, demonstrating that tumors co-expressing COX-2, iNOS, and TP are associated with increased metastatic potential and chemoresistance[24]. Yet, the work does not report on the key role of hypoxia-inducible factor-1α, which, in a hypoxic condition, directly stimulates iNOS, thereby incorporating oxygen deficiency into the inflammatory network[25]. Additionally, compensatory crosstalk—such as EP4 antagonism inadvertently increasing thromboxane levels-remains unexplored despite evidence that selective EP4 blockade can enhance TXA2 synthesis and counteract antitumor activity[24].

FUTURE DIRECTIONS

Future research needs to aim at receptor-specific targeting and clinical translation. The study should further include co-culture systems that more closely model the human tumor microenvironment, allowing correct modeling of mediator-stromal interactions. Lastly, biomarker-driven stratification according to eicosanoid profiles can potentially lead to the development of personalized therapies that modulate inflammatory signaling in lung cancer with enhanced efficacy and fewer adverse effects.

CONCLUSION

We concur with authors Demirel and Sinag[6] that nitric oxide, prostaglandins, and thromboxanes play a central role in lung carcinogenesis through immune modulation, angiogenesis, and tumor growth. Yet, an elaboration on receptor-specific mechanisms—e.g., EP and TP receptor signaling—and their downstream consequences would better define tumor-immune interactions. Enzyme expression differences (e.g., iNOS, COX-2) and compensatory feedback loops may differ by tumor type or patient population. Adding pathway-specific biomarkers, such as urinary Thromboxane B2 or PGE2 Levels, to functional imaging could better risk-stratify and monitor treatment.