Beyond killing cancerous cells, one of the major goals in traditional chemotherapy and radiotherapy treatment approaches has been to induce senescence in those cells that a therapy fails to kill outright. A senescent cell no longer replicates, and it is the uncontrolled replication of cancerous cells than makes cancer so dangerous. Therefore shutting down that replication was seen as a beneficial outcome, even if the cell survives. Over time, a greater understanding of senescent cells in the broader context of aging and age-related disease has led to a more nuanced view of therapy induced senescence in the context of cancer.
Senescent cells secrete inflammatory signals to attract the immune system, to make it pay attention to the local environment. But senescent cells also secrete pro-growth signals as a result of their role in regeneration following injury. The presence of some senescent cells for a short period of time is generally beneficial. The presence of many senescent cells for a lasting period of time is generally harmful. In the context of cancer, a small number of senescent cancer cells can help to engage the immune system in the process of killing cancerous cells. Too many senescent cancer cells can actually help the cancer by encouraging its growth and disrupting the operation of the immune system with excessive inflammatory signaling.
The established cancer therapies of chemotherapy and radiotherapy leave a burden of lingering senescent cells in cancer survivors. This is literally accelerated aging, and contributes to the higher risk of subsequent cancer and all cause mortality in those patients. It seems clear that the use of senolytic drugs to selectively destroy those lingering senescent cells should be beneficial, even though this has yet to be established as the standard of care. It is far less clear that using senolytic drugs during cancer therapy to kill senescent cells as they are created will be reliably beneficial. Whether it helps or hinders likely depends on factors that will be hard to determine and vary from patient to patient even for similar cancers.
When therapy-induced senescence meets tumors: A double-edged sword: A review
At present, it is widely recognized that conventional treatments for diseases such as cancer, including chemotherapy and radiation therapy, induce high levels of DNA damage in patient cells and lead to the secretion of numerous senescence-associated secretory phenotype (SASP) factors, thereby culminating in cellular senescence. This phenomenon is referred to as “therapy-induced senescence (TIS).” Chemotherapy, radiation therapy, and targeted therapies can promote cellular senescence in the tumor microenvironment (TME), affecting both cancer cells and their surrounding stromal cells. Prior investigations have shown that 31% to 66% of cancer tissues subjected to different types of chemotherapy display TIS. In addition, TIS has been quantified not only in malignant and nonmalignant fractions of tumor tissues but also in healthy tissue specimens after chemotherapy or radiation therapy. TIS is a common response to traditional cancer treatments. It was once considered a beneficial outcome of cancer therapy, and is currently regarded as a potential target for developing novel therapeutic approaches to inhibit cancer cells.
Tumor disease development, metastasis, medication resistance, and immunological evasion were all significantly influenced by the TME. It was used to assess the overall clinical outcomes of cancer treatment. Pharmacological induction may induce senescence in both malignant and nonmalignant tumor cells. In brief, TIS may affect the long-term prognosis of cancer by affecting TME. Significantly, the process of senescence triggers the activation of many pleiotropic cytokines, chemokines, growth factors, and proteases, which are together referred to as the SASP. This activation results in continuous arrest of tumor cells and remodeling of the tumor immune microenvironment. On the one hand, SASP can promote antitumor immunity and therapeutic efficacy; on the other hand, it can promote the infiltration of immune-suppressive cells, contributing to immune evasion by tumor cells. However, the specific effects of SASP in this context remain unclear.
The concept of a “one-two punch” approach for cancer treatment has been proposed, wherein the initial step involves the use of a drug to stimulate senescence in cancer cells and the second step involves the use of another drug (such as a senolytic) to eliminate senescent cancer cells. Cancer therapies stimulate senescence in both tumors and healthy tissues. Senescent cells are subsequently cleared through immune surveillance but may accumulate following cancer treatment. Despite the combination of traditional anticancer drugs and senolytics remaining in the early stages of research, reports have validated their effectiveness in suppressing tumor cells. Optimizing the beneficial effects of the SASP on the TME while mitigating its harmful effects, combined with therapeutic strategies that incorporate anticancer drugs, senolytics, and senomorphics, offers a promising new approach for future clinical treatments.
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