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Developmental Biology - HeLa Cells

Why do HeLa Cells Persist??

Cancer cells accumulate harmful mutations faster than they can be purged, so why don't they die out?...

Cancer first develops as a single cell going rogue, with mutations that trigger aggressive growth at all costs to the health of the organism. But if cancer cells are accumulating harmful mutations faster than the body can purge them, why doesn't the population eventually die out? To get to the heart of the matter, a team of scientists from Beijing and Taipei, China, probed the most famous cultured cancer cells, HeLa cells.

Famously isolated from cervical cancer victim Henrietta Lacks in 1951, her cancerous cells became the first immortal cancer cell line. HeLa cells have become a biotechnology resource for any in vitro drug development or cancer study. They have even helped in the development of the polio vaccine. Today, they are still providing ample opportunities to further understand cancer.

So how do cancer cells avoid complete genetic meltdown?
"In this study, HeLa cells are not used to reveal the process of tumorigenesis but as a model of cancer's underlying evolutionary force. We examined variation in growth rates among individual HeLa cells by monitoring clones from a common ancestral HeLa cell population."

Xuemei Lu PhD, Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Beijing; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming; University of Chinese Academy of Sciences, Beijing, China.

After first establishing a HeLa cell line (E6) from an ancestral cell line, the scientists expanded the cell population in culture. The team then sequenced the DNA of these clones to catalog all cell mutations observed. They focused on copy number variations (CNVs) rather than single DNA changes. Single-nucleotide mutations occur too slowly to produce significant DNA sequence variations given the short time of a cultured experiment.

"We then estimated the deleterious mutation rate and the average fitness decrease per mutation by performing computer simulations on individual cell growth," said author Hurng-Yi Wang of the Graduate Institute of Clinical Medicine, and Taiwan Institute of Ecology and Evolutionary Biology, National Taiwan University, Taipei, Taiwan, China.
The scientists found the main mutation is the affect on the copy number of genes — with an average of 0.29 harmful events for every cell division. Each of these harmful events reduced cell fitness by 18 percent.

The results indicate that diversity in cell growth can be generated in a very short period of time in cancer cells, are heritable as well as genetically determined.

"Our estimates indicate that HeLa cells experience a 5 percent reduction (0.29 × 0.18 ? 5%) in fitness for every generation. Our observations suggest that human cells that have been cultured for a sufficiently long period still generate deleterious mutations in the form of CNVs (copy number variations) at a high rate and high intensity. In such systems, a mutational meltdown might be plausible."

For example, when the scientists isolated 39 cells from B8 (a fast-growing clone) and 40 cells from E3 (a slow growing clone), monitoring their growth in a single cell for seven days — approximately 23 percent of B8 and 50 percent of E3 cells died out within those seven days. This due to either damage caused during cell isolation, or gene defects.

Most cell lines with growth rates less than 0.6 — died within 2 months. In total, only 60 percent of B8 and 27 percent of E3 cells survived for more than two months. Next, they picked about 20 cells from each of the single cell clones originated from B8 and counted their chromosome numbers.

Chromosome numbers varied far from the normal human number of 46. They ranged from 38 to 113 chromosomes. About 72 percent of these cells had between 55 and 70 chromosomes, which inndicates they were triploid. Despite single-cell origin, the progeny of these cell divisions quickly generated abnormal numbers of chromosomes (aneuploidy) after only 20-30 cell divisions — another frequent behavior of cancer cells. Yet, despite the level of cell mutations, reduction in growth rates and abnormal chromosome numbers, cancer cells still find a way to survive.

So how do HeLa cells persist?

According to Xuemei Lu PhD, "High deleterious mutation rates create the impression that HeLa cell lines should have gone extinct long ago."
Simulation results indicate that although most HeLa cells accumulated harmful mutations worse than their ancestral cells, there were still 13.1 percent that were mutation-free. These mutation-free cells keep the HeLa population from extinction."

Xuemei Lu PhD, Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Beijing, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China; University of Chinese Academy of Sciences, Beijing, China.

Which also explains why, even if chemotherapy treatment successfully killed 90 percent of a cancer cell population, it may still not be enough.

This new study not only advances our understanding of the evolution of HeLa cells, and tumors in general, but of cells of multicellular organisms in culture in general. In the future, the scientists want to exploit their cancer cell fitness and growth rate findings to understand how cancer cells can become even more vulnerable to recent breakthroughs using checkpoint inhibitor drugs.

This recent work is published in Molecular Biology and Evolution.

Large genomes with elevated mutation rates are prone to accumulating deleterious mutations more rapidly than natural selection can purge (Muller’s ratchet). As a consequence, it may lead to the extinction of small populations. Relative to most unicellular organisms, cancer cells, with large and nonrecombining genome and high mutation rate, could be particularly susceptible to such “mutational meltdown.” However, the most common type of mutation in organismal evolution, namely, deleterious mutation, has received relatively little attention in the cancer biology literature. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard the rate of cell proliferation. The main mutation events are copy number variations (CNVs), which, estimated from fitness data, happen at a rate of 0.29 event per cell division on average. The mean fitness reduction, estimated reaching 18% per mutation, is very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely face mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large enough. Because CNVs are common in most cell lines and tumor tissues, the observations hint at cancer cells’ vulnerability, which could be exploited by therapeutic strategies.

Yuezheng Zhang, Yawei Li, Tao Li, Xu Shen, Tianqi Zhu, Yong Tao, Xueying Li, Di Wang, Qin Ma, Zheng Hu, Jialin Liu, Jue Ruan, Jun Cai, Hurng-Yi Wang and Xuemei Lu.

© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model


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Jan 22, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Henrietta Lacks (born Loretta Pleasant; August 1, 1920 – October 4, 1951
died of cervical cancer. However, her cells live on today. Credit: Wikipedia

Phospholid by Wikipedia