Associate ProfessorMasumi Tsuda
Affiliation: Graduate Faculty of Medicine (Department of Medicine, School of Medicine)
Specialty: Tumor pathology
Research keywords: cancer stem cells, gene analysis, signal transduction, fluorescence bioimaging, hydrogel
Alma mater: Sapporo Minami High School (Hokkaido)
Final academic background: Graduate School of Medicine, Hokkaido University
HP address: http://patho2.med.hokudai.ac.jp/
*This article was originally published in the 4th issue of "Frontiers of Knowledge" and has been re-edited for the web.
Why do cancer treatments work for some people and not for others?
In Japan, 1 in 2 people will be diagnosed with cancer in their lifetime, and 1 in 4 people will die from cancer. Some of your family members, relatives, or even friends may have cancer and feel uneasy about it. If cancer develops, it is usually surgical resection (surgery) followed by radiation therapy, chemotherapy, and, if appropriate, targeted therapy. Recently, the number of cancers that can be completely cured by new molecular-targeted therapies is increasing. But why is it that some people still have the same cancer and are receiving the same treatment, but others are not. This is because, for example, even with the same breast cancer or the same colorectal cancer, the individuality (characteristics) of cancer cells differs from patient to patient (Fig. 1). Cancer cells have different properties in cancer tissue, and their properties change from moment to moment as the cancer progresses and is treated. In our laboratory, we are conducting research to elucidate such changes in the spatiotemporal properties of cancer from a molecular biological perspective, and to determine the optimal treatment for cancer patients.
Figure 1 “Cancer” has different characteristics depending on the patient.
For example, even if it is the same breast cancer, in patient A, proteins A, B, and C are expressed, and proteins A and C are activated (star shape). The B and D proteins are expressed, and the A and B proteins are activated (star-shaped). It is expected that the drug for A will have a therapeutic effect on both patients.
What are the ways to elucidate a cancer's personality?
Figure 2 CRKs (green) are localized to the cytoplasm and to the ends of the actin cytoskeleton (red).
Various research methods are necessary to elucidate the ever-changing properties of cancer cells. Compared to normal cells, cancer cells have acquired extremely strong proliferative, motility, and infiltration abilities, which allows cancer cells to continue to grow indefinitely, or to leave their original place of residence and metastasize to different organs. Masu. Such phenomena depend on the type, amount, nature, and activation state of proteins expressed in cancer cells.・Instructions (signals) are transmitted to enhance invasiveness (signal transduction). In order to investigate these, proteins are extracted from cells and subjected to biochemical assays, or histopathological immunostaining is performed. Among many proteins, we are conducting detailed research on the CRK (crack) adapter molecule. CRK functions as an adapter molecule that connects proteins and is involved in all aspects of cancer cell growth, adhesion, motility, and invasion (Fig. 2). Therefore, by targeting CRK as a therapeutic target, it is expected that it will be possible to suppress all the bad functions acquired by cancer cells. On the other hand, in order to investigate the dynamics of cancer cells, it is possible to fluorescently label proteins and cells themselves while the cells are alive, and to analyze them over time using a time-lapse microscope (fluorescence bioimaging). The quantity and properties of proteins may change depending on the state of the original nucleic acids such as DNA and RNA, and these are investigated using the latest next-generation sequencers (NGS) (gene analysis). We have so far performed genetic analysis using NGS in brain tumors, gastric cancer, colon cancer, pancreatic cancer, etc., and have found important gene mutations in cancer development and malignant transformation. By comprehensively evaluating these results, it is possible to clarify the properties of each cancer patient's cancer cells and determine the most effective treatment.
We aim to conquer cancer by eradicating cancer stem cells.
Figure 3 Cancer stem cells. When radiotherapy or chemotherapy (anticancer drugs) is applied to cancer, non-cancer stem cells (yellow, blue, and green in the left figure) die, but cancer stem cells (red) cannot be treated. It is not effective, and if even a little remains, it will eventually recur.
In recent years, it has been found that cancer tissues contain “cancer stem cells”, which are the bosses. Cancer stem cells hide themselves in cancer tissue, and it is not possible to identify which cells are cancer stem cells by looking at the tissue. The problem is that cancer stem cells show resistance to radiation therapy and anticancer drugs, in other words, they are difficult to treat. Even a small amount of cancer stem cells remaining after surgery or treatment can cause recurrence and treatment resistance (Fig. 3). Therefore, in order to conquer cancer, it is necessary to eradicate cancer stem cells, but since the number of cancer stem cells is small, it has been difficult to analyze the properties of cancer stem cells. Through joint research with Professor Gunn of Hokkaido University's Graduate Graduate School of Life Science, we have clarified that cancer stem cells can be efficiently induced in a short period of time by culturing cancer cells on a hydrogel. . If it is possible to increase the number of cancer stem cells using this method, it is expected that the properties of cancer stem cells will be clarified and it will be possible to provide molecularly targeted therapies suitable for each cancer patient (Fig. 4). In this way, we are working to elucidate various diseases, including cancer, by making use of the strengths of Hokkaido University, a comprehensive university, through interdisciplinary research with other fields and multidisciplinary fields.
Fig. 4 Cancer stem cell diagnostic model using hydrogel originally developed by Hokkaido University. By inducing cancer stem cells on the hydrogel and analyzing their properties, it is expected that appropriate therapeutic drugs can be determined for individual cancer patients.