Epidemiological evidence suggests that social interactions and especially bonding between couples influence tumorigenesis, yet whether this is due to lifestyle changes, homogamy (likelihood of individuals to marry people of similar health), or directly associated with host-induced effects in tumors remains debatable. In the present study, we explored if tumorigenesis is associated with the bonding experience in monogamous rodents at which disruption of pair bonds is linked to anxiety and stress. Comparison of lung cancer cell spheroids that formed in the presence of sera from bonded and bond-disrupted deer mice showed that in monogamous Peromyscus polionotus and Peromyscus californicus, but not in polygamous Peromyscus maniculatus, the disruption of pair bonds altered the size and morphology of spheroids in a manner that is consistent with the acquisition of increased oncogenic potential. In vivo, consecutive transplantation of human lung cancer cells between P. californicus, differing in bonding experiences (n = 9 for bonded and n = 7 for bond-disrupted), and nude mice showed that bonding suppressed tumorigenicity in nude mice (p<0.05), suggesting that the protective effects of pair bonds persisted even after bonding ceased. Unsupervised hierarchical clustering indicated that the transcriptomes of lung cancer cells clustered according to the serum donors' bonding history while differential gene expression analysis pointed to changes in cell adhesion and migration. The results highlight the pro-oncogenic effects of pair-bond disruption, point to the acquisition of expression signatures in cancer cells that are relevant to the bonding experiences of serum donors, and question the ability of conventional mouse models to capture the whole spectrum of the impact of the host in tumorigenesis.
Keywords: Peromyscus; bond disruption; cancer biology; deer mice; monogamous; pair bonds; polygamous.
People’s social interactions could influence their risk of developing various diseases, including cancer, according to population-level studies. In particular, studies have identified a so-called widowhood effect where a person’s risk of disease increases following the loss of a spouse. However, the cause of the widowhood effect remains debatable, as it can be difficult to separate the impact of lifestyle changes from biological changes in the individual following bereavement. It is not possible to use laboratory mice to identify a causal biological mechanism, because they do not form long-term relationships with a single partner (pair bonds). However, several species of deer mouse form pair bonds, and suffer from anxiety and stress if these bonds are broken. Naderi et al. used these mice to study the widowhood effect on the risk of developing cancer. First, Naderi et al. grew human lung cancer cells in blood serum taken from mice that were either in a pair bond or had been separated from their partner. The cancer cells grown in the blood of mice with disrupted pair bonds changed size and shape, indicating that these mice were more likely to develop cancer. This effect was not observed when the cells were grown in the blood of bonded deer mice or of another deer mouse species that does not form pair bonds. Naderi et al. also found that the activity of genes involved in the cancer cells’ ability to spread and to stick together was different in pair-bonded mice and in pair-separated mice. Next, Naderi et al. implanted lung cancer cells into the deer mice to study their effects on live animals. When cancer cells from the deer mice were transplanted into laboratory mice with a weakened immune system, the cells taken from pair-bonded deer mice were less likely to grow than the cells from deer mice with disrupted pair bonds. This suggests that the protective effects of pair bonding persist even after removal from the original mouse. These results provide evidence for a biological mechanism of the widowhood effect, where social experiences can alter gene activity relating to cancer growth. In the future, it will be important to determine whether the same applies to humans, and to find out if there are ways to mimic the effects of long-term bonds to improve cancer prognoses.
© 2021, Naderi et al.