Lung cancer–associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell–immune cell cross-talk

Abstract

Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, , and). In contrast, immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic () mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)-mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer-associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option.

Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

“…Cells were allowed to migrate for 6, 12, and 24 hours. Afterward, migrated cells were fixed, stained, assessed, and quantified with ImageJ software (NIH) (41,42).…”

Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders

“…Previous studies have shown that an increased RAD51C expression is associated with lung cancer [35]. Given that immune and inflammatory processes triggered by cancer cells can also lead to PH [36], it is intriguing to discover a significantly higher frequency of derived alleles in the No-HAPH group as compared with all the other populations (Fig. 3b).…”

Circular RNAs in the tumour microenvironment

“…Immune cells, which represent the most abundant cellular component of the TME, have been a target of interest for their potent cytotoxic capabilities [87][88][89]. The crosstalk among cancer cells, immune cells as well as released factors may be involved in the regulation of tumour immunity, and establish an environment that facilitate cancer development and progression [90,91].…”