Megan Sweet slices the tumor.
A typical day in the lab finds a Virginia Tech graduate student digging his hand deep into a refrigerated metal box and gradually moving a tumor grown in an attached mouse closer to a razor-sharp blade.
“It’s all about fine-tuning and making sure you get even slices,” said Sweet, who studies biological sciences.
Finally, the blade hits a clump of tissue the size of a pinky nail and rhythmically cuts through the tissue in clumps, clumps, clumps, clumps.
This is the most difficult and time-consuming part. But it’s also kind of meditative. ”
Megan Sweet, Virginia Tech graduate student
Slices of the tumor are so thin that they are translucent. Sweet carefully tap one on the glass slide. They will then stain specific cellular structures to better understand the structure of the tumor using a high-powered microscope.
Slice, stain, stare and compare – again.
These precise steps, repeated daily, provide a small but important moment of clarity in the still vague question of why some cancers are worse than others.
In this practice, Virginia Tech biologists are uncovering how tumors progress and evolve, with results published May 25 in the Proceedings of the National Academy of Sciences and earlier this year in Cancer Research.
Duplicate error
Most normal cells in the body are diploid. This means that there are two copies of each chromosome, one set from each parent..
To maintain health, diploid cells divide to create more diploid cells. However, sometimes dividing cells make mistakes that throw off the number of chromosomes. And, like mistakes on a printing press, those mistakes begin to repeat and accumulate.
This is one of the ways diseases such as cancer develop.
In collaboration with cell biologist Daniela Cimini, Sweet and graduate student Matt Bloomfield have spent the past five years analyzing cells with abnormal chromosome numbers, one of the proverbial killers of cancer.
To create the right environment for their research, members of Cimini’s research group caused diploid cancer cells to skip division while replicating their chromosomes. This resulted in so-called tetraploid cells, which have four complete sets of chromosomes.
These double-packed cells are not just a laboratory phenomenon. Even if tetraploidization occurs during human tumor development in the real world, it is not good news. It is associated with cancer progression and poor prognosis.
Tetraploid malignant tumor
But why do tetraploid cells make things so much worse?
To answer this, Sweet and Bloomfield compared tumors formed from diploid cancer cells to tumors formed from tetraploid cancer cells. They observed that during tumor formation in mice, the number of tetraploid cells actually decreased, yet the tumor mass rapidly expanded in size.
In a first-of-its-kind discovery, they found that this growth is driven by the recruitment of stromal cells (non-cancerous connective tissue cells). Provides structural support.
“The presence of even a small fraction of these tetraploid cells can promote the recruitment of extra non-cancerous cells that support further tumor progression,” Dr. Sweet said.
Cell size may predict tumor likelihood
The second study initially focused on the physiology of tetraploid cells. But when Bloomfield made human cancer cells tetraploid and isolated single-cell clones, he unexpectedly noticed that the cells in the first few clones were different in size.
They expected all the clones to be twice as large as normal diploid cells because of the extra material packed inside, but some were 25 to 30 percent smaller than expected.
And it just so happened that the smaller clones were more tumorigenic than the larger clones.
“The smaller clones are more aggressive,” Bloomfield said. “They grow faster, are more invasive, and are more resistant to common anti-cancer and stress-inducing drugs.”
Subsequent experiments in mice showed that tumors containing smaller tetraploid cells often grew more rapidly. Furthermore, the results were independent of cancer cell type, with the same behavior observed in colorectal and breast cancer.
But what about humans?
Using data from the Cancer Genome Atlas, a database containing thousands of annotated patient samples, the research team found that smaller tetraploid cells in some cancer types are indeed associated with poorer prognosis and lower survival rates.
“We already knew that tetraploidy could make cells more tumorigenic, but now we found that taking cell size into account allows us to more accurately predict tumor formation potential,” Cimini said.
Next steps include a deeper investigation of the mechanisms behind these findings and continued analysis of human cancer data.
Meanwhile, Sweet continues slicing.
sauce:
Reference magazines:
DOI: 10.1073/pnas.2522077123
