Adjuvant Immunochemotherapy with Protein-Bound Polysaccharide K for Colon Cancer in Relation to Oncogenic β-Catenin Activation

Kaname Yamashita1, Andrei V. Ougolkov1, 2, Hiroaki Nakazato3, Katsuki Ito3, Yasuo Ohashi3, Hidekazu Kitakata1, Kazuo Yasumoto1, Kazuhiko Omote1, Masayoshi Mai1, Yutaka Takahashi1 and Toshinari Minamoto1

(1) Division of Translational and Clinical Oncology (previously, Division of Diagnostic Molecular Oncology) and Surgical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
(2) Division of Developmental Oncology Research, Mayo Clinic, Rochester, Minnesota, USA
(3) The Study Group of Colon Cancer Immunochemotherapy with PSK and 5-FU (CIP), Aichi, Japan

Published online: 9 March 2007

Purpose Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic β-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating β-transducin repeat-containing protein. We investigated whether the activation state of β-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone.
Methods We assessed the activation states of β-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy.
Results We found two distinct patterns of nuclear accumulation of activated β-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type β-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type β-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type β-catenin activation.
Conclusions The presence of diffuse nuclear accumulation-type β-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.
Key words β-catenin - Colon cancer - Immunochemotherapy - Nuclear factor-kappaB - Protein-bound polysaccharide K

Supported by Grants-in-Aids for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture, from the Ministry of Health, Labor and Welfare, and from the Japan Society for the Promotion of Science.
Presented at meeting of the American Society of Clinical Oncology, New Orleans, Louisiana, June 5 to 8, 2004.
An erratum to this article is available at http://dx.doi.org/10.1007/s10350-007-0291-9.