Evolutionary theory could explain how some small malignant tumors are more likely to lead to secondary cancer than larger ones.
A paradoxical observation within oncology is that the mutations that lead to metastasis, or secondary cancer, often happen early on in the disease course, rather than later when a tumor has grown in size.
Researchers from the University of Pennsylvania believe this can be understood by applying evolutionary theory to tumors, which are in themselves diverse, dynamic populations.
Every tumor is made up of many different types of cells. The malignancy is actually a community of different types of cells, or lineages, with different roles. And if each of the lineages is subject to evolutionary pressures, they must compete against each other for resources in order to survive and thrive
It’s also important to note that to grow, tumors change their environment to make it better fit their needs. They can enhance blood-vessel formation and alter the structure and metabolism of nearby cells.
Metastasis happens when a particular type of cell sends molecules through the bloodstream to other parts of the body. Once they arrive, these molecules start preparing the new space, making it more suitable for cancer growth.
Erol Akcay, an assistant professor of biology in the School of Arts and Sciences, and Jimmy Qian, senior in the Molecular Life Sciences Vagelos Scholars Program at the University of Pennsylvania, created a computer model of a primary tumor made from four types of cancer cells, or lineages.
These were the cells that help construct the tumor’s immediate microenvironment; those that send molecules to distant, pre-metastatic sites; those that do both these tasks; and those that do not contribute to tumor growth at all.
The model included competitive interactions between all the subsets and various simulations were run.
While tumors were small, competition for resources between cells was low. This was when cells that contributed to the creation of pre-metastatic sites were more likely to be successful. As the tumor grew, they were more likely to be overtaken by the growing number of other types of cells.
Qian said this would predict that some smaller tumors were actually more likely to lead to metastasis, said Qian.
This is a finding supported by recent observations showing cancer cell mutations that arise early are more likely to be the source of metastatic disease.
Applying evolutionary theory to cancer tumors could allow clinicians to better predict how the disease could spread.
“Understanding how cancer evolves may help us to predict which lineage will come to dominate in a tumor and, possibly, preemptively treat that to minimize the chance for drug resistance,” said Qian.
“Or, if we can predict what sort of evolutionary mechanisms cause metastasis, we can try to tackle that before metastasis even starts.”
The study also suggests cancer therapies may benefit from considering a tumor as an ecosystem with clashing and cooperating populations of cells that could be manipulated to a patient’s benefit.
Qian JJ, Akçay E. Competition and niche construction in a model of cancer
metastasis. PLoS One 2018; 13(5):e0198163.