A new study from Tel Aviv University discovered changes in healthy lung tissue which indicate preparation to receive metastases. The changes were identified in the area known as “the micro-environment” of the tumor, and specifically in connective tissue known as fibroblasts. Researchers claim that these changes in the tissues are an early sign for the possible development of disseminated cancerous cells – metastases. According to them, understanding the metastatic process and its diagnosis at such an early stage may lead to life-saving prophylactic treatment.
The study conducted was led by Prof. Neta Erez, Chair of the Dept. of Pathology at the Sackler Faculty of Medicine, along with the research team of her laboratory, Dr. Ophir Shani and Dr. Yael Raz, as well as additional researchers from Tel Aviv University, Tel Aviv Medical Center (Ichilov), Sheba Medical Center and the Weizmann Institute. The paper was published in the journal eLife.
Researchers explain that in many types of cancers, among them breast cancer, patients do not necessary die from the primary tumor. In the end, the main cause of mortality are metastases, which arrive at the essential organs and proliferate there. Metastases may appear after several years even in patients who have undergone all the treatments offered, including surgical removal of the primary tumor, subsequent chemotherapy and radiation intended to destroy any residual tumor. Methods used for follow-up today locate metastases only when they are quite large – when the disease is at an advanced stage, and medicine does not have curative solutions.
For this reason, Prof. Erez’s research group is investigating the ‘black box’ – the time period between apparent recovery and the appearance of metastases, for the purpose of understanding the metastatic process and to identify it in early stages. Their research in the last years has revealed that designated tissues, in organs where the metastases are set to arrive, ‘prepare the area’ for reception and produce a hospitable environment for them, a long time before the appearance of the metastases themselves.
In the present study, the research team led by Prof. Erez searched for signs of these changes, which may be used in the future to identify the start of the process. The researchers focused on connective tissue cells known as fibroblasts which are found in the lungs among other places.
Prof. Erez: “In a normal situation, fibroblasts play a central role in healing wounds and injury to the lungs, but recent studies revealed that cancer is successful in recruiting them and causing them to produce a supportive environment for it. Within the framework of the present study, we performed sequencing of all the genes which are expressed (transcriptome sequencing) in fibroblasts taken from the lungs of mice in a model of breast cancer metastasis.”
The researchers compared the sequencing results sampled from healthy lungs, from lungs with micro-metastases (very small metastases which cannot be identified using existing clinical tools), and from lungs with large metastases, in a state of advanced disease. According to the changes identified from stage to stage, researchers have succeeded, for the first time, in characterizing the process occurring in the micro-environment of the metastases, already in the early stages of preparation of the area for its reception.
In addition, they specifically identified the proteins that initiate the ‘rewiring’ processes in fibroblasts, and discovered that one of the central proteins in the process is MYC – known as a central driver in accelerating the division of cancerous cells. This study revealed that MYC also plays an important role in the changes occurring in fibroblasts towards reception of the metastases.
Prof. Erez summarizes: “in our study, we have succeeded in characterizing processes which occur in lung tissue in preparation for the reception of breast cancer metastases. We believe that in the future, our findings can aid in the identification of the metastatic process even before the disseminated cancer cells thrive and colonize the metastatic organ, with the purpose of providing prophylactic treatment. Such treatment, that will prevent the development of metastases, may save the lives of millions of people, worldwide.”
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Subject of Research
Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity
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