A Virginia Tech cancer biologist has led an international, multi-institutional team to discover that an abnormal amount of chromosomes may be why certain cancers resist medical treatment.
Specifically, the team found that when certain cancer cells have abnormal amounts of chromosomes – a condition known as aneuploidy – they grow and adapt in conditions that are characteristic of a tumor’s environment. This includes within the presence of a chemotherapeutic drug.
“We found that cells with incorrect chromosome numbers grow better than cells with normal chromosome numbers when exposed to stress,” said Daniela Cimini, associate professor of biological sciences in the College of Science, a Fralin Life Science Institute affiliate, and a biology fellow at the Biocomplexity Institute of Virginia Tech.
The results were recently published in Scientific Reports.
In the study, the researchers exposed colon cancer cells with normal and abnormal numbers of chromosomes to conditions commonly found in the body when tumors form and grow. These environments include low nutrients, such as vitamins and proteins, and a lack of oxygen in a condition known as hypoxia.
Overall, the cancer cells with aneuploidy grew faster than normal cells.
The researchers also exposed the cells to a form of fluorouracil, a chemotherapeutic drug known on the market as Adrucil. Generally, the aneuploid cells continued to grow in the presence of the drug although at slower rates. Growth in cells with a normal amount of chromosomes was significantly slower in comparison.
In 2015, Cimini led another team to find that aneuploidy increases the diversity of chromosome number in daughter cells. These daughter cells then become more diverse in chromosome number, making a cell population with varying amounts of chromosomes, or a heterogeneous population.
According to the new study, this heterogeneity may provide aneuploid cells with specific advantages in adapting to certain environmental conditions, including resisting medical treatment.
“Aneuploid cells adapt to stressful conditions because they have an unstable genome that generates heterogeneous genomes and increases the probability of faster adaptation to challenging environments,” said Elsa Logarinho, director of the aging and aneuploidy lab at the Institute for Molecular and Cellular Biology in Porto, Portugal, and co-author of the study.
“By showing that aneuploid mammalian cells could have some selective advantages in some stressful conditions, this work will not only contribute to our fundamental understanding of how and whether aneuploidy contributes to the formation of tumors, but could also shed light into the mechanisms underlying emergence of chemotherapy resistance,” said Giulia Rancati, a group leader at the Institute of Medical Biology at the Agency for Science, Technology and Research in Singapore. Rancati was not involved in the research.
According to the study, aneuploidy may increase a cancer’s tolerance to these environmental conditions even after cells have formed tumors and become malignant, or lost growth control. Aneuploidy also increases the invasiveness of cancer cells regardless of these stressful environmental conditions.
“Our findings explain previous studies showing that higher rates of aneuploidy correlate with poorer prognosis,” said Cimini, the corresponding author of the study, and whose work is partly funded by the National Science Foundation. “Moreover, our findings suggest that taking into consideration the degree of aneuploidy may improve therapeutic strategies.”
Since the researchers tested aneuploid cells with specific chromosome alterations, future research can target how certain types of aneuploidy contribute to the formation of tumors. According to the researchers, these different types of aneuploidy can also serve as more specific targets for therapeutic strategies.
Cimini is also an affiliated faculty member with the BioTrans interdisciplinary graduate education program.
March 31, 2016