Abstract
The development of metastatic cancer is a multistage process, which often requires decades to complete. Impairments in DNA damage control and DNA repair in cancer cell precursors generate genetically heterogeneous cell populations. However, despite heterogeneity most solid cancers have stereotypical behaviours, including invasiveness and suppression of immune responses that can be unleashed with immunotherapy targeting lymphocyte checkpoints. The mechanisms leading to the acquisition of stereotypical properties remain poorly understood. Reactivation of embryonic development processes in cells with unstable genomes might contribute to tumour expansion and metastasis formation. However, it is unclear whether these events are linked to immune response modulation. Tumours and embryos have non-self-components and need to avoid immune responses in their microenvironment. In mammalian embryos, neo-antigens are of paternal origin, while in tumour cells DNA mismatch repair and replication defects generate them. Inactivation of the maternal immune response towards the embryo, which occurs at the placental–maternal interface, is key to ensuring embryonic development. This regulation is accomplished by the trophoblast, which mimics several malignant cell features, including the ability to invade normal tissues and to avoid host immune responses, often adopting the same cancer immunoediting strategies. A better understanding as to whether and how genotoxic stress promotes cancer development through reactivation of programmes occurring during early stages of mammalian placentation could help to clarify resistance to drugs targeting immune checkpoint and DNA damage responses and to develop new therapeutic strategies to eradicate cancer.
Highlights
Cancer is a multistage disease that affects millions of people on this planet
Tumours heavily rely on adaptive responses to DNA metabolism impairments for their continued proliferation as in the case of replication stress (RS), which can be defined as the presence of multiple alterations affecting DNA replication intermediates [4], and replication stress response (RSR) [5,6,7,8]
It would important to understand whether this is a common behaviour of cancer cells treated with agents inducing further genome instability and whether these signatures emerge in response to DNA damage occurring at earlier stages of cellular transformation. These findings might impact on our understanding of the effects of chemotherapy based on DNA damaging agents, which on the one hand kill proliferating cells, but on the other hand might contribute to activating pathways that are detrimental for residual cancer cells
Summary
Cancer is a multistage disease that affects millions of people on this planet. Development and progression of cancer can be driven by the acquisition of genome instability, which is facilitated by stressful conditions affecting the DNA replication process, including high proliferation rate, low DNA repair capacity and exogenous or endogenous insults to DNA. As cancer cells recapitulate several aspects of embryogenesis, including rapid proliferation and consequent RS, they could hijack the suppression mechanisms that embryos put in place against the maternal immune response towards fetal neo-antigens. Reactivation of trophoblastspecific pathways could contribute to the inactivation of lymphocyte-mediated control of tumour growth by repurposing pathways normally active during placenta formation and normally required to prevent maternal immune response against fetal antigens. This hypothesis posits that the so-called ‘pseudo-malignant’ trophoblast and cancer cells exploit comparable mechanisms at molecular level to achieve their proliferative, immunosuppressive and invasive processes [12,13,14]. We explore the possible links between solid cancer development and mammalian placentation that could have contributed to the display of cancer features
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