Jeong Hee Kim and Lintong Wu, two doctoral candidates in the Department of Mechanical Engineering at Johns Hopkins University, contributed to a study that examined an efficient screening method to detect therapy-induced senescent (TIS) cells that can increase the chance of therapy resistance and cancer relapse. This study, recently published in Science Advances, was in collaboration with researchers from the Polytechnic University of Milan and the National Research Council in Italy.
TIS cells are therapy-induced senescence, which means the gradual deterioration of functions. Another type of senescence is natural when cells deteriorate naturally as people age. For example, scars take longer to heal in aged cells because they do not go through the cell cycle — the growth and division process of cells — as easily as the young and healthy cells.
TIS cells are usually caused by cancer treatment. People with cancer often undergo radiotherapy, chemotherapy or a combination of both. The treatments target cancerous cells and promote cell death through apoptosis. Unfortunately, some treated cells can become TIS cells that are resistant to apoptosis and thus to cancer treatment. They withdraw from the cell cycle and enter a dormant state during which they can still negatively affect surrounding cells with proinflammatory factors and return to the cell cycle to become an even more aggressive type of cancerous cell.
Scientists initially believed that TIS cells are beneficial because they respond to cancer therapy by becoming dormant. However, recent discoveries indicate that TIS cells can increase cancer relapse. Either the cancer returns to the same part of the body or migrates elsewhere, even after patients complete their treatment course.
Kim reflected on the opposing evidence on TIS cells’ role in cancer treatment in an interview with The News-Letter.
“Contemporary researchers attribute this recurrence of cancer to TIS cells, which did not die during the treatment and facilitated relapsing of cancer or provided breeding ground that promotes cancer. Scientists still have not reached consensus whether TIS cells help cancer therapy or not,” Kim said.
To uncover the mysteries of TIS cells, Kim and Wu’s team used HepG2 cells — human cancer cells in the liver. The HepG2 cells tend to form a small spheroid or a cluster of cells, making it difficult to visualize every single cell in an image. It is more challenging to differentiate cells when they are stacked together than when they are in a monolayer.
To address this problem, the group devoted themselves to optimizing the methodology in order to make each cell more discernible in images. In response to this cluster growing property of HepG2 cells, the group also changed their data analysis method to better characterize and measure cell properties such as volume and dry mass.
“After several heated debates with our advisor, Professor Ishan Barman, and between teammates, we finally reached a consensus on the methods that we are going to use for measuring the properties of HepG2 cells,” Wu said in an interview with The News-Letter.
The team looked for imaging methods that would be able to visualize TIS cells activity when they are alive. This could enable timely detection of TIS cells and introduce opportunities to better understand cellular mechanisms of TIS cells and their roles in cancer treatment. Therefore, the researchers selected label-free techniques because they do not require chemical staining. Staining cells multiple times would not allow the researchers to see the natural status of the cells. The three label-free techniques chosen are coherent anti-Stokes Raman scattering, optical diffraction tomography and multiphoton absorption.
Combining these cutting-edge label-free microscopy techniques showed ability to detect TIS manifestation as early as 24 hours and revealed clear visualization of HepG2 cancer cells’ cellular and organelle activities in their natural state. These can become scientists’ tools to better understand TIS cells’ role in cancer treatment and more efficiently detect them in the future. The ability to screen for TIS cells at an early stage can increase patients’ chances of receiving timely treatment and preventing future cancer recurrence.
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