On the relationship between good intentions and less-than-good results
A cancerous tumor develops due to the uncontrolled division and proliferation of cells that have undergone a cancerous transformation. However, in the tumor’s environment there are normal body cells (eg immune system cells and fibroblasts – fibrous cells in the body’s connective tissue), as well as the extracellular matrix (matrix) structure and blood vessels. All of these are “reprogrammed” by the cancer cells to help them spread and metastasize.
Prof. Neta Erez from the Faculty of Medicine at Tel Aviv University and her team investigate the environment of the cancerous tumor, mainly in the breast, and its contribution to its spread, that is, to the development of metastases. “Most deaths from cancer are caused by metastases that cannot be cured,” says Prof. Erez. “So, for example, in breast cancer, after the patients undergo surgery to remove the tumor, they usually receive complementary treatment (such as chemotherapy and radiation) to eliminate any cancerous remnants that may have remained. And yet, sometimes, after a few years, metastases are discovered in some of them, for example in the lungs or bones. These are metastases that were not observed before in the imaging tests because they were tiny – micro-metastases. I mean, for all the years they were there, but failed to prosper. Over time they learned to ‘communicate’ with a new microenvironment, for example cells in organs other than the breast. Then, after a few years, when they are discovered, it is already too late, they are simplified and it is very difficult to cure the disease.”
Prof. Erez and her team focus their research on the micrometastases stage. Their purpose is to prevent their formation and the development of the tumor or its recurrence. In these studies, they inject cancer cells into the breast of mice, surgically remove the tumor that has developed, and examine the sequence of events in the time window when metastases develop in distant organs (for example, bones, lungs and brain).
In their latest study, which won a research grant from the National Science Foundation, they wanted to know how fibroblasts help the tumor spread or the development of metastases. In a normal state, fibroblasts play a central role in healing damage (such as wounds) in tissues and maintaining their structure. After an injury, the fibroblasts activate immune cells (inflammatory cells) that trigger a local inflammatory response, and in addition create scar tissue.
The researchers isolated fibroblasts from the breast cells of the mice and tested them with genetic sequencing. This is how they discovered the genes that are expressed in the different stages of breast cancer development, and their level, and in the process found a significant increase in the level of proteins that belong to the inflammasome pathway. This pathway is recognized by the cells of the immune system: its proteins allow them to sense tissue damage and call additional immune cells to produce inflammation that will fight the damage. But to date it has not been observed in fibroblasts.
“In order for the immune system to activate an inflammatory response, it needs to recognize specific proteins, for example from a bacterium, or a virus, or tissue damage caused by an injury,” says Prof. Erez. “We were surprised to discover that fibroblasts act in a similar way in a cancer process – they sense, through the inflammasome proteins found on them, the chemical and mechanical damage that the tumor causes to the tissues and interpret this as damage caused by an injury.
Thus, they multiply, recruit inflammatory cells to the area (something that encourages cancerous transformation), and also secrete substances that increase the permeability of the blood vessels of the healthy cells, which allows the cancer cells to penetrate them more easily and send metastases. In other words, just as the fibroblasts help injured tissue to heal, so they help the tumor to thrive.”
The researchers discovered that the cytokine (a protein that promotes inflammation) interleukin 1 beta – which is secreted by the fibroblasts (and which is the final product of the inflammasome pathway) – is the one that actually affects the recruitment of inflammatory cells and the permeability of blood vessels in a way that promotes the formation of metastases. In mice that underwent genetic silencing of the inflammasome pathway in fibroblasts, and especially of interleukin 1 beta – the breast tumor grew less and the formation of metastases was delayed. The researchers hope that this finding can be used to develop drugs that will block the inflammatory pathway in fibroblasts and thus reduce breast tumors and other tumors and even prevent the development of metastases.
Life itself:
Neta Erez, 49, married + two children (16.5, 13), lives in Nes Ziona, likes to cook and do yoga. In 2020, she received a Mentoring in Science award from the prestigious journal Nature (“Beyond being a researcher, it is very important to me to promote students and young scientists and support their growth and careers. In my opinion, this is one of our most important roles as experienced researchers”).
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