The cells that can mobilize for breast cancer (upper row) form a spherical shape and appear less densely packed than their neighbors, as compared with resting cancer cells (lower row) with the same shape and size over time. Image credit: Soft Matter Physics Division Leipzig, Steffen Grosser
The tumor cells tend to be clustered in the early stages of development. As the tumor grows, however, specific cells break out of the cluster and move to distant regions in the body. This process, also known as metastasis, is why most cancers become fatal (see Targeting metastasis to stop the spread of cancer). If there was an easy, fast method to detect these restive cells early, the doctors and patients could have more time to tailor treatment plans.
In an upcoming investigation published in Physical Review X, scientists of Leipzig University in Germany potentially made the first steps towards this goal by identifying a manageable list of criteria for determining the breast cancer cells that can be mobilized under a microscope. This is an early stage in the development of metastasis. They have nuclei that are longer and smaller in size than their counterparts, as compared to the immobile tumor cells. According to the senior writer and physicist of soft matter Josef Ka, finding mobile tumor cells in biopsies may one day assist oncologists in identifying high-risk patients before cancer spreads,
When doctors are the majority to detect cancer, they tell patients that it is likely to spread once it is metastasized from a local tumor lymph node nearby. However, invading lymph nodes isn’t a good indicator of diagnosis, Kas says. The study reveals that among women who develop distant tumors, 30% will never create cancerous lymph nodes. For those who experience cancer and infiltrate lymphatic tissue, around 1/3 will never have distant tumors develop in other areas of their body. The current study sought an improved biomechanical marker for cell mobility.
In the field of physicists studying cancer, researchers typically discuss groups of cells as “jammed,” meaning that particles are packed so tightly together that they cannot move. They are also “unjammed,” meaning that cells can move together and swap positions as they slide over one another. Kas and his group, along with other physicists investigating asthma and cancer in the past decade, studied the unjamming of cells. In the latest study, Kas and collaborators wanted to document clinically how unjamming is an integral part of the metastatic process. “This is the first time soft matter physics may enter the clinic,” Kas declares.
The project began with digital scans of paper-thin slices from tumors taken from 1,380 breast cancer patients. Each piece was between 3 and 5 micrometers thick and contained one layers of cells. The lead author Pablo Gottheil, a doctoral student in Kas’s group, measured the shape of cells, nucleus shape, and size of cells using computer vision and machine learning algorithms. He discovered that the space between the adjacent cells increased dramatically for cancer patients to spread.
Nowadays, when doctors attempt to evaluate the prognosis of patients, they take into consideration the size of the tumor, its degree, and whether it has spread into lymph nodes. When Gottheil incorporated his biomarkers into the existing prognosis models, he discovered an increase of 26% in the accuracy of predicting outcomes of the 1,380 patients. To illustrate this, he suggests, imagine that a physician has two patients and is trying to determine which one is more at risk. By using established risk indicators, a doctor will be able to make the right prediction a certain percent often. If the doctor were to consider the biomarkers that indicate cell mobility, they would be successful 26% more often, Gottheil states. Clinical follow-up trials are required to establish if these conclusions are held across a wider array of samples and in a broader range of cancer. If they succeed, Kas hopes that cell-to-cell density and nuclear lengthening could one day be used as easy tests for diagnosing pathology in labs across the globe.
The Tumor Biologist Michael Rogers at Harvard Medical School and Boston Children’s Hospital in Massachusetts is calling this research interesting. Cancer is often viewed by biological and chemical signaling according to him. It’s important to look at it as a result of mechanical forces. It’s also important to establish the cells that have an increased risk of the spread of cancer and the possibility of death, says.
However, Rogers is one of the few who has a reluctance to apply the concept of “cellular unjamming” to this situation. The phenomenon the researchers observed, he claims, should not be explained as the fluid dynamic “when a developmental description is better supported in the literature.”
Rogers believes that interactions between adjacent breast cancer cells keep them in place. He observes that breast cancer cells can move as sheets in the initial stages of the development of tumors with tight junctions among the cells of neighbors. As cancer progresses, however, the cells are known to lose some of their communication ability and become disorganized, in a process called epithelial-mesenchymal transition, or “EMT.” Rogers suspects that the increase in cellular mobility over time is just an intermediate step in breaking epithelial cell junctions. “In other words, what they describe as unjamming looks like dedifferentiation or EMT to me and the latter processes are much better understood in the cancer context,” Rogers states. However, he applauds the research paper for identifying an approach to identify the cells with a high likelihood of metastasis.