Senescent tumor cells: an overlooked adversary in the battle against cancer

Abstract

Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.

Fig. 1. STCs in various cancer tissues.

Multiple types of primary cancer tissue were processed to make fresh frozen sections for SA-β-Gal staining. Hematoxylin or nuclear fast red were used for counterstaining. Arrows indicate SA-β-Gal-positive STCs.

Fig. 2. Cancer-promoting features of STCs.

STCs participate in cancer progression by releasing various types of SASPs. Three key features are increased cancer invasiveness, enhanced cancer stemness, and a modulated immune cell microenvironment.

Fig. 3. Targeting of STCs vs. SASPs.

The left and right sides indicate senolytics and senomorphics, respectively. The numbers indicate the corresponding references.