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Department of Pathology and Oncology
Juntendo University School of Medicine
Research Theme
1. Understanding roles of Cancer associated fibroblasts (CAFs) to promote tumor malignancy.
2. Elucidation of maintenance mechanism of cancer promoting ability and regulation mechanism of cell diversity of CAFs
3. Development of new cancer therapy targeting CAFs
Outline of research theme
1. Understanding roles of Cancer associated fibroblasts (CAFs) to promote tumor malignancy.
It is known that CAFs act on nearby cancer cells through the production of various growth factors and cytokines to promote the growth and progression of cancer.
Our research group showed that stromal cell-derived factor 1 (SDF-1/CXCL12) secreted by CAFs acts in an endocrine manner on endothelial progenitor cells (EPCs) derived from bone marrow expressing CXCR4 receptor and promotes the angiogenesis by recruiting EPCs to the cancer mass. Also the SDF-1 acts in a paracrine manner on neighboring breast cancer cells to promote the tumor progression (Fig. 1; Orimo A. et. al, Cell, 2005; Orimo A. and Weinberg RA, Cell cycle, 2006).
Fig. 1
It is not clear which single cancer cells that have undergone complete EMT (epithelial-mesenchymal transition) or clusters composed of cancer cells with cell adhesion ability contribute to invasion and metastasis. Recently, several groups have reported that cancer cell clusters are more essential for invasion and metastasis than single cancer cells because they enhance cell death resistance. However, many of these studies have examined with cancer cell lines or cancer cells derived from model mice. Which invade and metastasize in patient cancer, a single cancer cell or a cancer cell cluster? Is the process mediated by EMT? In order to clarify the above questions, our group subcutaneously transplanted human colon cancer fragments dissected from 40 colorectal cancer patients into immunodeficient mice. Then, the tumors developed from the tumor fragments “patient-derived tumor xenografts (PDXs)” were removed, and the dissociated into cell suspensions to be injected into the rectal mucosa of secondary mice. 13 cases formed cancers by orthotopic transplantation, and 8 cases of them spontaneously formed metastases in the liver and lungs (Fig. 2; Mizukoshi K., et al., Int J Cancer, 2020).
Fig. 2
subcutaneous
implantation
orthotopic
injection
Immunohistochemical study of primary and metastatic lesions of patients with colorectal cancer and PDX revealed the following metastasis model. (Fig. 3 ;Mizukoshi K.,et al., Int J Cancer, 2020). E-cadherin-positive cancer cells (E type) that exhibited epithelial state and E-cadherin and ZEB1 co-positive cancer cells (E/M type) indicating the hybrid epithelial/mesenchymal state were found in the primary lesion. These tumor cells formed clusters, locally invaded, were detected in peripheral blood, and contributed to the formation of metastases in distant organs. Moreover, the metastasized E/M type cancer cells promoted metastatic colony formation via MET (mesenchymal- epithelial transition). The E/M state in the tumor cell clusters presumably contributes to their collective dissemination and seeding metastasis.
Fig. 3
It has been reported that stimulation from the tumor microenvironment promotes invasion and metastasis of cancer cells. However few studies have focused on the involvement of cancer cell cluster formation and the tumor microenvironment. Furthermore, how CAFs promote cancer invasion and metastasis is controversial and unconfirmed. Recently, we revealed that CAFs induce partial EMT in cancer cells and promote invasion and metastasis through the formation of cancer cell clusters (Fig. 4; Matsumura, et al. Life Sci Alliance, 2019)).
Human breast cancer cells and CAFs were co-implanted into immunodeficient mice, and the implanted cancer cells were extracted from the tumor mass formed. These cancer cells acquired the properties of highly epithelial (E-cadherinhiZEB1lo/neg: Ehi) type and hybrid epithelial/mesenchymal (E-cadherinloZEB1hi: E/M) type by SDF-1 and TGF-β derived from CAFs.
The clusters composed of these two type breast cancer cells acquired cell death resistance and high invasive/metastatic traits. These clusters formed metastases in the lung by invading and disseminating through blood vessels. Also, E/M type cancer cells boosted metastatic colonization of the lungs via MET.
Fig. 4
It is known that the phenotypes of E/M and Ehi types and high invasive/metastatic traits induced by CAFs are stably maintained in cancer cells. Further elucidation of the molecular mechanism by which CAFs induce heterogeneity (at least Ehi, E/M type) in cancer cells, and epigenome reprogramming cause of stably high invasive/metastatic traits is in progress.
2. Elucidation of maintenance mechanism of cancer promoting ability and regulation mechanism of cell diversity of CAFs
It is known that CAFs stably maintain the cancer promoting ability. However, its molecular mechanism is unknown. We have previously shown that breast cancer-derived CAFs acquire SDF-1 and TGF-βsignals in an autocrine manner in the process of cancer progression in order to induce and maintain activated myofibroblast and cancer promoting ability. (Fig. 5; Kojima et al., PNAS, 2010). In addition, it has been reported in human cancer that CAFs are formed from multiple subpopulations such as myofibroblasts and inflammatory fibroblasts by the recent development of single cell analysis. The composition of these subpopulations is predicted to change dynamically in the course of cancer progression by stimulation from the cancer microenvironment. However, the regulatory mechanisms of the composition of these subpopulations are poorly understood. Studies are underway to identify regulators of subpopulation composition and to better understand their relationship to phenotypic plasticity of CAFs.
Fig. 5
3. Development of new cancer therapy targeting CAFs
CAFs are expected to serve as target cells for cancer therapy because they have the effects of promoting cancer growth, invasion and metastasis. In consideration of the significance of CAFs subpopulations, we are working on the identification of agents that induce CAFs growth inhibition and cell death.
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