Prognostic implications of cellular senescence in resected non-small cell lung cancer

Background: Cure and long-term survival for non-small cell lung cancer (NSCLC) remains hard to achieve. Cellular senescence, an emerging hallmark of cancer, is considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells can paradoxically affect the surrounding tumor microenvironment (TME), ultimately leading to cancer relapse and metastasis. As such, the role of cellular senescence in cancer is highly controversial. Methods: In 155 formalin-fixed paraffin-embedded (FFPE) samples from surgically resected NSCLC patients with pathological tumor-node-metastasis (pTNM) stages I-IV (8th edition), cellular senescence was assessed using a combination of four immunohistochemical senescence markers, i.e., lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67, and correlated to clinicopathological parameters and outcomes, including overall survival (OS) and disease-free survival (DFS). Results: A tumoral senescence signature (SS) was present in 48 out of 155 NSCLC patients, but did not correlate to any clinicopathological parameter, except for p53 mutation status. In a histologically homogenous patient cohort of 100 patients who fulfilled the following criteria: (I) one type of histology, i.e., adenocarcinoma, (II) without known epidermal growth factor receptor (EGFR) mutation, (III) curative (R0) resection and (IV) no neoadjuvant systemic therapy or radiotherapy, the median OS and DFS for patients with a tumoral SS (n=30, 30.0%) compared to patients without a tumoral SS (n=70, 70.0%) was 53 versus 141 months (P=0.005) and 45 versus 55 months (P=0.25), respectively. In multiple Cox proportional hazards (Cox PH) model analysis correcting for age, pTNM stage I-III and adjuvant therapy, a tumoral SS remained a significant prognostic factor for OS (HR =2.03; P=0.014). Conclusions: The presence of a tumoral SS particularly based on high p16INK4a expression significantly affects OS in NSCLC adenocarcinoma. In this light, adjuvant senolytic therapy could be an interesting strategy for NSCLC patients harboring a tumoral SS, ultimately to improve survival of these patients

Cellular senescence in cancer: clinical detection and prognostic implications

Abstract Cellular senescence is a state of stable cell-cycle arrest with secretory features in response to cellular stress. Historically, it has been considered as an endogenous evolutionary homeostatic mechanism to eliminate damaged cells, including damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, accumulation of senescent cells can cause long-term detrimental effects, mainly through the senescence-associated secretory phenotype, and paradoxically contribute to age-related diseases including cancer. Besides its role as tumor suppressor, cellular senescence is increasingly being recognized as an in vivo response in cancer patients to various anticancer therapies. Its role in cancer is ambiguous and even controversial, and senescence has recently been promoted as an emerging hallmark of cancer because of its hallmark-promoting capabilities. In addition, the prognostic implications of cellular senescence have been underappreciated due to the challenging detection and sparse in and ex vivo evidence of cellular senescence in cancer patients, which is only now catching up. In this review, we highlight the approaches and current challenges of in and ex vivo detection of cellular senescence in cancer patients, and we discuss the prognostic implications of cellular senescence based on in and ex vivo evidence in cancer patients