RESEARCH

[ Introduction | Current projects  ]

 2010-2014參與之專題研究計畫 (research projects involved between 2006 ~ 2012)：

擔任主持人之計畫 (Projects as principal investigator (PI))：

Introduction

[ Chinese Version ]

      During the past few years, my research has been focusing in exploring new protocol to increase the efficacy of cancer therapy.  These works can be simply divided into three directions.  The first is to explore the potential of using IL-3-directed cancer immunotherapy to enhance the efficacy of radiation therapy.  I have been working on this project more than 10 years.  Throughout this period, I have clearly demonstrated that IL-3 gene expression can enhance the effects of radiation therapy in three murine tumor models, FSAR fibrosarcoma, FSAN fibrosarcoma, and TRAMP-C1 prostate cancer.  Those works have been published in 3 high ranking journals. One is in Cancer Research (Chiang, CS et al, 1997) and two are in Cancer Gene Therapy (Chiang, CS et al, 2000 and Tsai, CH et al, 2006).  I do not only illustrate that the potential of using IL-3 gene therapy to enhance the curing rate of radiation therapy, but also demonstrate the working mechanism on IL-3 by altering macrophage activity, which has been published in the Journal of Leukocyte Biology (Wu, YZ et al, 2000).  The recent publication in Cancer Gene Therapy (Tsai, CH et al, 2006) provides a new protocol of using Tet-On inducible vector to minimize the side effects of IL-3, which sets up a foundation to clinical application.  During these years, I have established my own niche on the pre-clinical application of IL-3.   Throughout these researches, I have also noticed that macrophages play vital roles in both cancer therapy and CNS disease because the main responsible cell for IL-3 effects is macrophage, no matter is in tumor or brain microenvironments.  This has lead to my current research topics of targeting macrophages to enhance the efficacy of radiation therapy.

      The second research area is the study of molecular changes of normal tissue following radiation therapy.  I began this project on the study of brain tissues while I was Ph.D. student in UCLA.  After coming back to NTHU, I cooperated with Prof. Hong, JH, Chang-Gung Memory Hospital, to focus on the study of the molecular response of lung tissues to radiation therapy.  Our studies on radiation-induced molecular changes of lung tissues have been published in several important journals in the field of radiation biology research such as two papers in Internal Journal of Radiation Oncology Biology Physics and one paper in International Journal of Radiation Biology. After these years, we have built up our research reputation on radiation-induced molecular changes of normal tissues, in particular brain and lung tissues.

      The third research area is the study of Cordyceps sinensis (CS), a traditional Chinese Herbal Medicine, as healthy remedy following cancer treatment.  I have never been in Chinese Medicine area until 2003.  The effects of CS on immune modulation functions have been well reported before I got into this area, but most publications were in low ranking journals, which were only read by small society.  My first proposal to the Council of Agriculture was with the intension to extend the CS value from the application in traditional Chinese Medicine to in Western Medicine.  I was luckily being appreciated by the committee in the condition without any experience and records on Chinese Medicine. With the efforts of my first Ph.D. student, Liu, WC, we have demonstrated that CS could enhance the recovery of immune function by overcoming the immune-suppression caused by primary tumor and cancer therapy agents such as radiation or chemotherapeutic drugs.  Two recent papers demonstrate that CS not only enhances the recovery of radiation-induced bone marrow and intestine damages (Liu, WC et al, 2006), but also taxol-induced leucopenia and immune-suppression (Liu, WC et al, 2008).  The SCI of these two papers is well above the average SCI value (1.57±0.71) of CS-related articles published in last 10 years. It has been more difficult than our original plan to extend CS applications beyond Chinese Medicine because of complex formula of CS or Chinese medicine. Although our publications in journals of Radiation Research and Experimental Biology Medicine are a small step while just comparing their SCI with other publications, this has been a big step for the study on Chinese Herbal Medicine. Our 3^rd publication with another Ph.D. student, Li, CY, who is co-mentored by Prof. Hsu, IC, and me, on this topic has just been accepted for the publication in the Journal of Leukocyte Biology (Lee, CY et al, 2009).  The publication in the Journal of Leukocyte Biology (SCI: 4.128) is another milestone for the study on Cordyceps sinensis because this will be an important article that scientifically demonstrates the Yin-Yang nature of CS, which depends on the status of host physiological condition. In another word, this is the first demonstration of the belief in Chinese Herbal Medicine that it can be a healthy supplement to boost host immunity for healthy person and also be a medicine to treat disease for patients suffered from over-reactive immune reactions. It is worth to mention that the highest SCI article about CS research published before this article is by Chen, YC et al in the Int J Biochem Cell Biol (SCI: 4.009), 2005.    

        These three areas seem un-related at a first glance, but they do have a central common theme when the details are examined. The central theme is macrophages.  Perhaps, it is fair to say that I always have eyes on macrophages, which also explain why I began my Chinese Herbal Medicine with CS because prime target cell of CS effects is also macrophages.  Macrophages are not only the responsible cells to IL-3 effects, no matter in the brain or tumors, but also major players in radiation-induced normal tissue response.  Furthermore, our works on CS have also demonstrated that CS effects are through the influence of bone marrow stem cell differentiation toward monocytes/macrophage lineage. My recent publication in International Journal of Immunology (Chiang, CS et al, 2008) has demonstrated that macrophages are double faces and very flexible in adapting to microenvironmental changes, which provide a new avenue for the manipulation of macrophages toward therapeutic advantages.  The idea of using “TAM as target and vector for cancer radiotherapy” was derived from those previous experiences on macrophages.  This novel hypothesis has recently been approved by the review committee of National Health Research Institute (NHRI) and been awarded for 3 years (2009/01/01 ~ 2011/12/31).  I have also obtained an award for receiving 3 NHRI grants in last 10 years.  The study on TAMs has also become my current and future research direction.  Our past research aimed to license a formula for conditioning macrophages toward hypoxic tumors has initiated an multiple discipline integrated grant (跨領域整合型計劃) and been awarded by the NSC for three years (2010/08/01~ 2013/07/31).

Current Projects

[ Chinese Version ]

1. 

Therapeutic platform for radiation-induced invasive brain tumor

(放射治療後周邊浸潤小島腫瘤微環境之研究與治療)

2013/08/01 ~ 2016/07/31

High grade gliomas (WHO grade III-IV) are the most frequent and common type of malignant brain tumors in adults and persist as serious clinical problems. Unlike the remarkable improvement in survival rate of breast cancer, melanoma, and prostate cancer, the curing rate of high grade glioma remains poor and barely improves in last 10 years.  Although patient's survival rate depends on the histological grade of the tumor, glioma cell invasion into adjacent normal brain regions, so called invasion tumor front or infiltration islands, is believed to be the major reason for the failure of these tumors to treatments including neurosurgery, radiation therapy (RT), and chemotherapy.  To understand the behaviors of tumor invasion and target the invasion by new form therapies becomes very important in treating high-grade gliomas. A suitable pre-clinical animal brain tumor model is thus required.  PI’s lab has recently established a new murine astrocytoma tumor model, ALTS1C1.  The ALTS1C1 cells have been proved to be a good brain tumor model similar to human brain tumor and to fit into these purposes.  Using this murine tumor model, we have demonstrated that primary tumor core and invasion tumor front have different tumor microenvironments. Furthermore, our recent preliminary data showed that conventional radiation therapy (RT) reduces the tumor burden of primary tumor core as anticipated, but as compared to control tumors, tumor invasiveness and angiogenesis are enhanced in the invasion tumor front and infiltration islands.  These results are same as the failure pattern when high-dose RT was given in human brain tumor.  In this project, we aim to investigate factors that are associated with distinct tumor microenvironment in the invasion tumor front of ALTS1C1 tumors and contribute to the distinct response to RT.  The factors identified in the invasion tumor front can provide information for designing new therapeutic protocol to enhance RT effects.  To achieve this goal, three specific aims are proposed.  They are:

(1)      To establish a pre-clinical invasive brain tumor model for the research aiming on designing therapeutic strategy against invasive brain tumor.

(2)      To explore the effects of radiation therapy alone or concomitant with TMZ therapy on the microenvironments of invasion tumor front.

(3)      To develop a multiple therapeutic platforms using bone marrow-derived monocytes as cellular carrier to deliver therapeutic nanoparticles as adjuvant therapy.

Throughout this study, we anticipates establishing a therapeutic platform to target RT-induced invasive brain tumors and providing a new therapeutic protocol for the treatment of high grade glioma.

Key words: glioma, radiation therapy, tumor microenvironment

2. 

Double faces of NO-polarized M2 TAMs in recurrent tumors

(探討一氧化氮極化的M2型腫瘤巨嗜細胞在復發腫瘤中的雙重特性)

 2012/01/01 ~ 2014/12/31

NO produced by M1 tumor-associated macrophages (TAMs) is a critical mediator for the cytotoxic activity of TAMs against cancer cells.  Conversely, NO produced by M2 TAMs could promote tumor progression. The local concentration of NO was frequently used to explain this biphasic nature of NO, but the threshold concentration has never been determined. In my current NHRI IRG (2009/1/1 ~ 2011/12/31), entitled “TAMs: target and vector in cancer radiotherapy”, we found that the inhibition of NO production by NOS inhibitor, L-NAME, could enhance the efficacy of radiation therapy (RT), but diminish the therapeutic effect of IL-3-mediated prodrug therapy.  Using two treatment protocols, RT and tk/GCV therapy, we found that both therapies could cause non-iNOS expressing M2 TAMs to express iNOS, but they have different effects on tumor growth.  This indicates that the effect of NO on TAMs is not only dependent on local concentration, but also nearby microenvironmental context.  The complexity of the NO signaling pathway and its dependence on environmental context gives us pause before concluding that the inhibition of NO production by TAMs is a promising therapeutic strategy for all tumors or therapies.  Thus, a more thorough molecular understanding of NO signaling in TAMs and tumor microenvironments after different therapies with divergent responses to NO-associated therapies is necessary. In this renewal grant, we aim to examine the hypothesis that different microenvironments resulted from different treatment protocols or different types of tumors can influence the effects of NO-polarized M2 TAMs on tumor growth.  The success of this study will be the first to demonstrate that the opposite role of NO on tumor growth depends on the environmental factors nearby TAMs.  To achieve this goal, three specific aims are proposed.

1.          To illustrate the molecular signaling pathways of NO on TAMs function.

2.          To identify effective factors that are responsible for the opposite effects of NO-polarized M2 TAMs in recurrent tumors of tk/GCV therapy.

3.          To verify whether the roles of NO-polarized M2 TAMs in recurrent prostate tumors also occur in glioma.

3.

( 發展仿生性多分子自組裝聚合體與奈米金顆粒作為超音波與巨嗜細胞主導的腫瘤治療藥劑)

2010/08/01 ~ 2013/07/31