Exploring the links between cancer and placenta development

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.

Keywords: DNA damage response; DNA repair; cancer.

Figure 1.

Emergence of cancer features by selection. Mutagenesis, oncogene activation, loss of functional BRCA1/2, accumulation of RS and loss of p53-mediated tumour barrier might predispose to hyper-mutagenesis-mediated emergence of clones that are positively selected for their ability to evade immune response and invade tissues.

Figure 2.

Emergence of cancer features by reactivation of embryonic pathways: Mutagenesis, oncogene activation, loss of functional DNA repair genes such as BRCA1/2, accumulation of RS, activation of RS-induced inflammatory pathways mediated by cGAS-STING and loss of ATM/p53-mediated tumour barrier might induce epigenetic changes predisposing to re-emergence of stemness and embryonic-like features alongside hyper-mutagenesis, which could boost this process. Full activation of trophectoderm-like properties might predispose to immune evasion and tissue invasion.

Figure 3.

Parallels between placenta and solid tumour formation: solid cancer resembles placenta development in several aspects, including the formation of new vessels, and the ability to invade surrounding tissues and to evade the immune responses. Tumour microenvironment could be populated by cells similar to the ones found in the feto-maternal interface, where EVT invades the maternal tissues, including immunoregulatory T-reg cells.