Programs of scientific research are ever short of funding, and this profoundly steers both the operation of these individual programs, as well as the standards for various fields of research that emerge via consensus and collaboration. Consider that the primary driving force behind most choices in the use of animal models of disease is the matter of reducing cost and time. Artificial models that turn out to have too little a connection to the real condition, or that mislead research in ways that sabotage progress, emerge time and time again because of the imperative to run studies more rapidly and at a lower cost. Young animals with forms of damage or toxicity or genetic disability are used to replicate the phenotypes of diseases that develop slowly in genetic normal old individuals. Assumptions about mechanisms are baked into the animal models. Alzheimer's disease and many cancers are the most prominent examples of conditions in which the well-established models are highly artificial and often questionable in comparison to the real conditions they are mimicking, but these are by no means the only examples.
Today's research materials provide an example of the sort of gap in knowledge that can arise when only young mouse models are used in work on cancer, a predominantly age related condition. Melanoma is a very well studied form cancer, and at this point once of the least threatening given recent advances in immunotherapy. Nonetheless, while the way in which melanoma risk changes with age in humans is well characterized, little investigation has taken place in mice to attempt to understand why this pattern of incidence exists - as that research requires a greater cost in time and funding in order to use old mice. Thus when researchers do in fact find that funding, they tend to discover new information. Melanoma is a relatively well controlled cancer in the grand scheme of things, but consider the many other far worse forms of cancer in which this same story is playing out over the years with different details.
Older Mice May Offer New Insight Into Cancer and Aging
Cancer risk increases with age and is often more aggressive and difficult to treat in older adults. However, fewer than 10% of mouse studies use aged animals, with most relying on mice roughly equivalent to humans in their early 20s. This discrepancy is one potential reason so many cancer drugs that show promise in preclinical models go on to fail in human trials. New research suggests melanoma behaves differently with age. The data showed cancer spread was the lowest in young mice, peaked in middle-aged mice, and declined in very old mice.
Researchers suggest that a key factor involves a specific group of immune cells called gamma delta (γδ) T cells, which act like early warning guards that help prevent cancer from spreading. Young and very old mice had more of these protective immune cells, and their cancer was more likely to stay dormant or spread less. Middle-aged mice had fewer γδ T cells, and their melanoma was far more likely to spread to organs like the lungs and liver. The study also showed that melanoma cells themselves can actively weaken the immune system as animals age. In middle-aged mice, melanoma released certain molecules that shut down or exhaust γδ T cells, allowing previously quiet cancer cells to "wake up" and spread aggressively. Notably, when researchers removed γδ T cells from young and very old mice, melanoma spread increased, suggesting these immune cells normally help keep the cancer in check. By contrast, blocking immune-suppressing signals restored immune protection and reduced cancer spread, but only in middle-aged mice.
Abstract 2072: Role of the aging on the ᵧδ; T-cells in metastatic cutaneous melanoma progression.
Melanoma incidence, metastasis, and mortality are significantly associated with age. Interestingly within the clinic, melanoma incidence is low in young adults, peaks between ages 65-79, and decreases thereafter (79+). This phenomenon has never been studied as pre-clinical studies predominantly focus on young (8-week-old) mouse models. Here, syngeneic melanoma cells have been injected into C57Bl/6 young (8 weeks), aged (12 months) and geriatric (18-24 months) male mice. Spleen, lungs, and liver have been collected to analyze metastasis and immune infiltration by flow cytometry. Histological analysis has been performed to quantify the number of metastases and to determine different immune markers (e.g. CD45, CD8, CD4).
Our data highlighted that middle aged mice had significantly increased γδ T cell infiltration in the metastatic lung and liver relative to young and geriatric mice, which had less metastasis. Based on this, we used a γδ T cell mouse model of depletion coupled with depletion antibodies against gamma delta in young and geriatric mice respectively. Our preliminary data indicated that upon reactivation in middle-aged mice, melanoma cells secreted PROS1, which drives cancer proliferation. Its effects on the immune system within our model have not been studied. We overexpressed PROS1 in melanoma cells, injected them, and analyzed metastasis and γδ T cell infiltration. Our data shows that middle-aged mice have significantly increased lung and liver metastasis relative to young mice. Interestingly, geriatric mice have lower levels of metastasis, replicating what is seen in the clinic.
Age induced decrease of γδ T cell infiltration in middle-aged mice, induced largely by PROS1 secretion from melanoma cells, promotes aggressive metastases. Adoptive treatment with γδ T cells or use of a PROS1 inhibitor may be a viable therapeutic option for metastasis in elderly individuals.
View the full article at FightAging
