Research Activities

To develop new preventive and therapeutic methods for treating cancer, it is necessary to stress the importance of elucidating the mechanisms of cancer progression. Most of recent studies based on molecular biology have focused on the mechanisms of cancer proliferation, anti-apoptosis, and immortalization by studying the alteration of genes and signal transduction in cancer cells. However, cancer must originate from a single cell surrounded by predominantly non-cancerous cells, either parenchymal or mesenchymal cells, from the first step of cancer initiation through invasion and metastasis, and only cancer cells that can adapt to the microenvironment are able to survive, proliferate and form malignant tissue. This is supported by many clinicopathological findings that represent specific mutation profiles in cancers with organ specificity and the presence of organ-specific metastasis of human cancers. Thus, cancer-microenvironment interactions must play an important role in cancer progression, proliferation, invasion and metastasis. We aim to elucidate the importance of cancer microenvironment interactions in cancer progression, invasion and metastasis and to produce new diagnosis and treatment methods for cancer, as follows.
:1) Cancer-microenvironment interaction:
Cancer tissues are composed of not only cancer cells, but also various stromal cells, such as fibroblasts, blood vessels, lymph vessels, pericytes, macrophages, and other inflammatory cells. Although the focus has always been on the characterization of cancer cells, characterization of these stromal cells and their origins and physiological functions have not yet been elucidated. We established an animal model to clarify the origin of these stromal cells and found that the cancer stromal fibroblast origins were hereterogeneous and that their physiological functions in cancer progression varied. We will further elucidate the importance of cancer stromal cells of various origins in cancer biology. In addition, we are now striving to identify a new cancer stem cell marker and to elucidate the interaction between cancer stem cells and cancer stromal cells in order to clarify the underlying mechanisms of cancer progression.
:2) Development of a new therapy for organ-specific cancer invasion and metastasis:
Metastasis of cancer is achieved through multiple steps, starting with cancer cell dissociation from the primary site, stromal destruction and invasion, vessel infiltration, lodging in a distant organ, and proliferation at the metastatic organs. Organ-specific metastasis is frequently observed in breast, prostate, colon, stomach and lung cancers. We established a new animal model for elucidating the mechanism for colon cancer liver metastasis, prostate and breast cancer bone metastasis and found organ-specific metastasis to be due to the adaptation and survival of cancer cells in the metastatic organs. We are now endeavoring to develop a new therapy for organ-specific cancer metastasis.
:3) Elucidation of the mechanisms for cancer pain, cancer fatigue and cachexia:
Most cancer patients suffer from various cancer-associated conditions, such as cancer pain, fatigue and cachexia. The underlying mechanisms for these cancer-associated symptoms are complicated and have not yet been elucidated. Our research is now focused on establishing a new animal model to investigate the mechanisms in order to understand the cancer-associated symptoms, such as cancer pain, fatigue and cachexia.
:4) Establishment of a new concept for the diagnosis of biopsy specimens for individualized cancer treatment:
Specimens taken from cancer tissues for diagnosis provide important information not only about cancer cells but also about cancer patients. To establish individualized cancer-patient treatments, a new concept for diagnosing biopsy specimens is needed. We investigate how and which information is obtained from gene expression, protein expression and image analysis using biopsy samples and are identifying factors which are correlated with the patient’s clinical outcome to establish a new integrated method for diagnosis based on biopsy specimens.

Literature

1) Ishii G, Ito TK, Aoyagi K, Fujimoto H, Chiba H, Hasebe T, Fujii S, Nagai K, Sasaki H, Ochiai A. Presence of human circulating progenitor cells for cancer stromal fibroblasts in the blood of lung cancer patients. Stem Cells. 2007.
2) Goya M, Ishii G, Sangai T, Kodama K, Miyamoto S, Hasebe T, Nagai K, Yonou H, Hatano T, Ogawa Y, Ochiai A.
Prostate-specific antigen contributes to the osteoblastic phenotype via apoptosis of osteoclast precursors: Potential role in osteoblastic bone metastases of prostate cancer. The Prostate 1,66(15):1573-84, 2006.
3) Sano A, Sangai T, Maed H, Nakamura M, Hasebe T, Ochiai A. Kallikrein 11 expressed in human breast cancer cells releases insulin-like growth factor through degradation of IGFBP-3. Int J Oncol. 30(6):1493-8, 2007.
4) Ito TK, Ishii G, Chiba H, Ochiai A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene. 2007 May 21; [Epub ahead of print]

Other Activities

The Japanese Society of Pathology
The Japan Cancer Association
Japan Society for Head and Neck Cancer Japanese Gastric Cancer Association
The Japan Esophageal Society
Japanese Society for Cancer of the Colon and Rectum
The Japanese Gastroenterological Association
The Japan Society of Clinical Oncology
American Association for Cancer Research
International Academy of Pathology
Others

Future Plan

One of our research goals is to develop a new diagnosis and treatment method. We must obtain information not from cancer cells, but about cancer cells and their microenvironment because the cancer-microenvironment interaction must be important not only in cancer cell biology but also for gathering information about the cancer patients. Understanding the mechanisms and developing a new treatment for cancer pain and cancer fatigue are also important future goals.

Messages to Students

Recent advances in molecular biology have given us deep insights into cancer cells, and have also allowed small but steady progress in the field of cancer diagnosis and treatment, though many cancer patients are still suffering from this disease and mortality remains high. We must continue to make progress in order to understand cancer and to develop new treatments.
“Science tells as what we can know, but what we can know is little, and if we forget how much we cannot know we become insensitive to many things of very great importance.” - Bertrand Russell