Life after Cell Death—Survival and Survivorship Following Chemotherapy

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  Figure 1. Pathways to Relapse. Chemotherapy-induced relapse includes intrinsic cancer cell resistance, reprogramming and selection, and pro-metastatic changes downstream of somatic cell responses. Cancer cell resistance include overexpression of drug efflux pumps, to actively transport cytotoxic chemicals out of the cancer cell, increased EMT, invasion and adhesion properties, and secretion of extracellular vesicles that prime distant organs (left). Somatic cells in the tumour microenvironment or at distant, tumour-free organs undergo changes in response to chemotherapy. Vascular dysfunction has been shown to contribute to the risk of metastasis and relapse, due to the loss of barrier integrity and resulting vessel leakiness, increasing endothelial activation and a more inflammatory, pro-tumour microenvironment. Chemotherapy also rewires secretory profiles and metabolic preferences, changes in nutrient and substrate availability, which can play into cancer-specific adaptations, often potentiating proliferation and colonisation at secondary sites. Created with BioRender.com (accessed on 5 June 2021) [69].

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  Figure 2. Tomorrow’s problem. Chemotherapy is associated with severe side effects including multi-organ failure. The best characterized side effect of therapy is cardiotoxicity, which can become apparent immediately or in the years following therapy, in severe cases leading to chronic heart failure and death. Endothelial cell apoptosis or activation can lead to increased risk of thrombotic events. Cancer patients also commonly experience chemotherapy-induced cognitive impairment, which may be the result of neurotoxicity, neuroinflammation, BBB breakdown, oxidative stress, and indirectly, cardiac insufficiency. Bone loss due to vascular defects, oestrogen deficiency or resident cell senescence, leads to an increased risk of fractures in patients. Damage to the gut lining and microbiome underlies not only typical nausea and digestive problems, but also systemic inflammation, endotoxin release and subsequent organ damage; Chronic hepatic and renal insufficiency are commonly associated with chemotherapy, and risk for these co-morbidities is compounded by multiple factors, which include loss of vasoregulation and vessel narrowing leading to ischemia, fibrosis and inflammation. After…