Michiyo Kodama

Bio: Michiyo Kodama is an academic researcher from Hiroshima University. The author has contributed to research in topics: Cancer & Lymphangiogenesis. The author has an hindex of 12, co-authored 24 publications receiving 854 citations.

Mesenchymal stem cells enhance growth and metastasis of colon cancer.

Abstract: Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed α-smooth muscle actin and platelet-derived growth factor receptor-β as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.

Involvement of Proinflammatory Cytokines IL-1β and IL-6 in Progression of Human Gastric Carcinoma

Abstract: Gastric carcinoma occurs in response to chronic inflammation of gastric mucosa infected with Helicobacter pylori. It is not known how cytokines affect the growth and progression of gastric carcinoma. Materials and Methods: We measured tissue concentrations of the proinflammatory cytokines interleukin (IL)-1‚ and IL-6 in gastric carcinoma and investigated the correlation between the levels of these cytokines and clinicopathological features. Biopsy specimens of tumors or adjacent normal mucosa were obtained from 42 Japanese patients with gastric carcinoma. Tissue levels of IL-1‚ and IL-6 were measured by enzyme-linked immunosorbent assay. Results: IL-1‚ levels were significantly higher in the neoplasm than in the corresponding normal mucosa. The IL-6 levels in the neoplasm correlated significantly with the depth of invasion and lymphatic invasion. High levels of IL-1‚ and IL-6 were characteristic of non-scirrhous type gastric carcinoma. Conclusion: These results suggest that IL-1‚ and IL-6 are involved in the growth and progression of human gastric carcinoma. Gastric carcinomas express a variety of growth factors/ cytokines and their receptors that regulate tumor growth and development in an autocrine manner (1). Growth factors/cytokines mediate interactions between tumor cells and host cells, and they function as paracrine factors for endothelial cells and stromal fibroblasts to promote angiogenesis and fibrosis (2, 3). We and others have reported that gastric carcinoma cells secrete various cytokines (4-6), which play central roles in both cellular and immune responses. Interleukin (IL)-1 is expressed by a variety of malignant tumor cells (7-9), and diverse effects on the growth of solid tumors have been reported. IL-1 inhibits the growth of melanoma and breast and ovarian carcinomas (9-11), whereas IL-1 stimulates the growth of gastric and colorectal carcinomas (4, 12, 13). There are two IL-1 proteins, IL-1· and IL-1‚. These proteins bind to the same receptors and have agonistic roles (14). There are no significant differences in the spectrum of activities induced by IL-1· and IL-1‚ in in vitro and in vivo assays (14). IL-6 is a multipotent cytokine that has several immunological activities including induction of several acute phase proteins and regulation of proliferation and differentiation of immunocompetent cells (15). IL-6 has also been implicated in the pathogenesis and/or prognosis of several different tumors, including multiple myeloma, lymphoma, ovarian cancer, prostate cancer and renal cell carcinoma (16-20). Ito et al. (4, 5) reported that IL-1 and IL-6 are secreted by gastric carcinoma cells and that they stimulate growth of these cells in vitro. However, the relationship between levels of these cytokines in gastric carcinoma tissues and clinicopathological data has not yet been clarified. In the present study, we measured tissue concentrations of IL-1‚ and IL-6 in human gastric carcinoma and the correlation with various clinicopathological features. Materials and Methods Patients and tumor specimens. This study included 42 randomly selected Japanese patients with primary gastric carcinoma who underwent surgery or endoscopic mucosal resection at Hiroshima University Hospital, Japan between 1996 and 1998. The patients ranged in age from 39 to 83 years (mean 62.5 years). Of these patients, 19 (45.2%) had stage I disease, 9 (21.4%) had stage II disease, 9 (21.4%) had stage III disease and 4 (9.5%) had stage IV disease. Pathological data for the entire study group is given in

Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor β is associated with lymphatic metastasis in human gastric carcinoma.

Abstract: Recent study of murine fibrosarcoma has revealed that platelet-derived growth factor (PDGF) plays a direct role in promoting lymphangiogenesis and metastatic spread to lymph nodes. Thus, we investigated the relation between PDGF and PDGF receptor (PDGF-R) expression and lymphatic metastasis in human gastric carcinoma. We examined PDGF-B and PDGF-Rβ expression in four human gastric carcinoma cell lines (TMK-1, MKN-1, MKN-45, and KKLS) and in 38 surgical specimens of gastric carcinoma. PDGF-B and PDGF-Rβ expression was examined by immunofluorescence in surgical specimens and in human gastric carcinoma cells (TMK-1) implanted orthotopically in nude mice. Groups of mice (n = 10, each) received saline (control) or PDGF-R tyrosine kinase inhibitor imatinib. PDGF-B and PDGF-Rβ mRNA expression was significantly higher in patients with lymph node metastasis than in those without and was also significantly higher in diffuse-type carcinoma than in intestinal-type carcinoma. In surgical specimens, tumor cells expressed PDGF-B, but PDGF-Rβ was expressed predominantly by stromal cells. Under culture conditions, expression of PDGF-B mRNA was found in all of the gastric cell lines, albeit at different levels. In orthotopic TMK-1 tumors, cancer cells expressed PDGF-B but not PDGF-Rβ. PDGF-Rβ was expressed by stromal cells, including lymphatic endothelial cells. Four weeks of treatment with imatinib significantly decreased the area of lymphatic vessels. Our data indicate that secretion of PDGF-B by gastric carcinoma cells and expression of PDGF-Rβ by tumor-associated stromal cells are associated with lymphatic metastasis. Blockade of PDGF-R signaling pathways may inhibit lymph node metastasis of gastric carcinoma.

Immune response to CagA protein is associated with improved platelet count after Helicobacter pylori eradication in patients with idiopathic thrombocytopenic purpura.

Abstract: Background: Improvement in platelet counts has been reported after eradication of Helicobacter pylori in patients with idiopathic thrombocytopenic purpura (ITP). We examined the levels of serum markers of gastritis and anti-CagA (cytotoxin-associated gene A) IgG antibody in patients with ITP to investigate whether these factors are associated with the platelet response after H. pylori eradication therapy. Materials and methods: One hundred and sixteen consecutive patients with ITP were assessed for H. pylori infection by 13C-urea breath test and serum H. pylori antibody test. Patients with H. pylori infection received eradication therapy. Before and after eradication therapy, we evaluated serum levels of gastrin, pepsinogen (PG)-I, and PG-II and the anti-CagA IgG antibody titer. Results: H. pylori infection was found in 67 (58%) of the 116 patients with ITP. Fifty-two infected patients received eradication therapy, which was successful in 44 patients (85%). Twenty-seven patients (62%) showed an increased platelet count and were identified as responders. The duration of ITP was shorter in responders than in nonresponders (p = .017). There was no difference of the levels of gastrin and PGs between responders and nonresponders. Before eradication therapy, the serum anti-CagA antibody titer did not differ significantly between responders and nonresponders. However, reduction in the anti-CagA antibody titer after eradication therapy was significantly greater in responders than in nonresponders (p = .013). Conclusions: H. pylori eradication therapy improves the platelet count in H. pylori-positive patients with ITP of short duration. Immune response of hosts to CagA protein of H. pylori may play a role in the pathogenesis of ITP.

Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms.

Abstract: Purpose: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells. Experimental Design: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA microarrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice. Results: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors. Conclusions: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.

Inflammation: gearing the journey to cancer.

Abstract: Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis.

Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth.

Abstract: Cancer tissues are composed of cancer cells and the surrounding stromal cells (e.g., fibroblasts, vascular endothelial cells, and immune cells), in addition to the extracellular matrix. Most studies investigating carcinogenesis and the progression, invasion, metastasis, and angiogenesis of cancer have focused on alterations in cancer cells, including genetic and epigenetic changes. Recently, interactions between cancer cells and the stroma have attracted considerable attention, and increasing evidence has accumulated on this. Several researchers have gradually clarified the origins, features, and roles of cancer-associated fibroblasts (CAFs), a major component of the cancer stroma. CAFs function in a similar manner to myofibroblasts during wound healing. We previously reported the relationship between CAFs and angiogenesis. Interleukin-6 (IL-6), a multifunctional cytokine, plays a central role in regulating inflammatory and immune responses, and important roles in the progression, including proliferation, migration, and angiogenesis, of several cancers. We showed that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions. Furthermore, CAFs contribute to drug-resistance acquisition in cancer cells. The interaction between cancer cells and the stroma could be a potential target for anti-cancer therapy.

Concise Review: Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth?

Abstract: The discovery that mesenchymal stem cells (MSCs) are recruited into tumors has led to a great deal of interest over the past decade in the function of MSCs in tumors. To address this, investigators have used a variety of tumor models in which MSCs are added exogenously to determine their impact on tumor development. Interestingly, many studies have reported contradicting results, with some investigators finding that MSCs promote tumor growth and others reporting that MSCs inhibit tumor growth. Many mechanisms have been reported to account for these observations, such as chemokine signaling, modulation of apoptosis, vascular support, and immune modulation. In this review, we analyzed the differences in the methodology of the studies reported and found that the timing of MSC introduction into tumors may be a critical element. Understanding the conditions in which MSCs enhance tumor growth and metastasis is crucial, both to safely develop MSCs as a therapeutic tool and to advance our understanding of the role of tumor stroma in carcinogenesis.

Cancer Stem Cell Niche: The Place to Be

Abstract: Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies.