Kazuyoshi Shiga

Bio: Kazuyoshi Shiga is an academic researcher from Nagoya City University. The author has contributed to research in topics: Medicine & Cancer cell. The author has an hindex of 7, co-authored 15 publications receiving 624 citations.

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.

Apigenin induces apoptosis by suppressing Bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer.

Abstract: Apigenin is a natural flavonoid that exhibits anti-proliferative activity and induces apoptosis in various types of cancer, including colon cancer. The aim of the present study was to determine the mechanism underlying the apoptosis-inducing effect of apigenin in colon cancer. Apigenin reduced the proliferation of colon cancer cell lines, stimulated the cleavage of PARP and induced apoptosis in a dose-dependent manner. Apigenin treatment also suppressed the expression of the anti-apoptotic proteins Bcl-xL and Mcl-1. Small interfering RNA was used to knockdown Bcl-xL and Mcl-1 expression alone and in concert, and the proliferation and apoptosis of cancer cells were subsequently measured. The knockdown of Bcl-xL and Mcl-1 expression together markedly suppressed cell proliferation and induced apoptosis. Apigenin treatment also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which targets Bcl-xL and Mcl-1. The results of the current study therefore determined that apigenin induces the apoptosis of colon cancer cells by inhibiting the phosphorylation of STAT3 and consequently downregulates the anti-apoptotic proteins Bcl-xL and Mcl-1.

High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab

Abstract: We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer (CRC) who underwent bevacizumab-containing chemotherapy. In this retrospective study, the pretreatment serum IL-6 and plasma vascular endothelial growth factor (VEGF) levels were measured in 113 patients with metastatic CRC. The cut-off values for these measurements, as determined by a receiver operating characteristic curve analysis, were 4.3 and 66 pg/mL, respectively. The median follow-up period was 19 months (range 1–40 months). Sixty-three patients had primary cancer, and 38 had a metachronous recurrence. Thirty patients underwent curative resection, and 71 underwent chemotherapy, 53 of whom received bevacizumab-containing chemotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier and multivariate Cox proportional hazards regression analyses. The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes. However, high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels. A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome. In patients with metastatic CRC, high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance.

Suppression of Cancer-associated Fibroblasts and Endothelial Cells by Itraconazole in Bevacizumab-resistant Gastrointestinal Cancer.

Abstract: Background We evaluated the ability of itraconazole to enhance the effects of bevacizumab in bevacizumab-resistant cancer cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Materials and methods Human gastrointestinal cancer cell lines (HT-29, MKN-28 and MKN-45), human umbilical vein endothelial cells (HUVECs), and CAFs established from human colon cancer were used. In each of these cell lines, cell growth, apoptosis, and angiogenesis were evaluated with bevacizumab with and without itraconazole both in vitro and in vivo. Results Itraconazole suppressed HUVEC growth by apoptosis through inhibition of mitogen-activated protein kinase and ribosomal protein S6 kinase signaling. Itraconazole also suppressed monocyte chemoattractant protein-1 secretion and the growth of CAFs. In xenografts, compared to monotherapy with either agent alone, combined treatment with itraconazole and bevacizumab significantly reduced tumor volume, tumor weight, and microvessel density. Conclusion Itraconazole-dependent suppression of endothelial cell and CAF growth resulted in synergistic effects with bevacizumab in bevacizumab-resistant cancer cells.

Targeting the tumour stroma to improve cancer therapy

Abstract: Cancers are not composed merely of cancer cells alone; instead, they are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote the resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistromal agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment

Abstract: Nanovehicles can efficiently carry and deliver anticancer agents to tumour sites Compared with normal tissue, the tumour microenvironment has some unique properties, such as vascular abnormalities, hypoxia and acidic pH There are many types of cells, including tumour cells, macrophages, immune and fibroblast cells, fed by defective blood vessels in the solid tumour Exploiting the tumour microenvironment can benefit the design of nanoparticles for enhanced therapeutic effectiveness In this review article, we summarized the recent progress in various nanoformulations for cancer therapy, with a special emphasis on tumour microenvironment stimuli-responsive ones Numerous tumour microenvironment modulation strategies with promising cancer therapeutic efficacy have also been highlighted Future challenges and opportunities of design consideration are also discussed in detail We believe that these tumour microenvironment modulation strategies offer a good chance for the practical translation of nanoparticle formulas into clinic

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.

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

Abstract: The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

Tumor-Derived Exosomes and Their Role in Cancer Progression.

Abstract: Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.