A View of Cellular Senescence in Cancer
Cellular senescence is a double-edged sword in the matter of cancer. A cancer cell turned senescent, and thus entered a state of growth arrest, is not a cancer cell that continues to replicate. It secretes pro-growth, pro-inflammatory signals that draw the attention of the immune system. This can be beneficial, helping to defeat a cancer, particularly in the early stages. After a certain point, however, too much cellular senescence aids the cancer in further growth. While it seems clear that senolytic treatments to remove lingering senescent cells are wholly beneficial after a cancer is defeated, it isn't clear that the same is true of senolytic treatment conducted before or during cancer therapy. As this paper notes, whether clearance of senescent cells during cancer therapy is beneficial or harmful may vary from patient to patient, even for the same type of cancer.
Clinical evidence of cellular senescence in cancer patients has long been underestimated, in part due to the difficult detection, since currently no specific and universal markers for senescent cells exist. Historically, cellular senescence was primarily considered as an endogenous tumor suppressor mechanism halting the proliferation of damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, during the last two decades, a more nuanced view on the involvement of cellular senescence in tumorigenesis and response to therapy has emerged.
Here, we provided a comprehensive overview on the prognostic implications of cellular senescence in cancer patients with solid tumors. Increasing clinical evidence add to the antagonistic pleiotropy of cellular senescence as differential prognostic outcomes, ranging from improved to impaired outcome, are demonstrated. In a simplified model we propose that the prognostic implications of oncogene-induced senescence (OIS) as well as therapy-induced senescence (TIS) are highly context-dependent and primarily depend on the senescence burden, the secretion and the composition of the senescence-associated secretory phenotype (SASP) and/or duration of SASP presence, thereby providing a rationale for the differential outcomes of OIS as well TIS observed within the same cancer type as well as between different types of cancer.
The detection of cellular senescence in cancer patients can be achieved by various methods and using various markers. Despite clear algorithms to accurately assess and quantify senescent cells in vitro and in vivo, a plethora of different senescence markers, single or combined with other markers, are currently used to demonstrate the presence of cellular senescence. Hence, it is difficult to compare clinical data and to draw reliable conclusions regarding the prognostic implications of cellular senescence, as well as the implementation of emerging senolytics (i.e., targeted removal of senescent cells) and senomorphics that modify/suppress the SASP, underlining the need for a uniform and consistent application of recognized and validated markers of cellular senescence.