Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic beta-catenin activation.
OBJECTIVE
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 beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-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 beta-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 beta-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 beta-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 beta-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 beta-catenin activation.


CONCLUSIONS
The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.
Yamashita
Kaname
K
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, Japan.
Ougolkov
Andrei V
AV
Nakazato
Hiroaki
H
Ito
Katsuki
K
Ohashi
Yasuo
Y
Kitakata
Hidekazu
H
Yasumoto
Kazuo
K
Omote
Kazuhiko
K
Mai
Masayoshi
M
Takahashi
Yutaka
Y
Minamoto
Toshinari
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011509:Proteoglycans / Q000008:administration & dosage*; D015996:Survival Rate; D051996:Transcription Factor RelA / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000964:Antimetabolites, Antineoplastic; D011509:Proteoglycans; D051996:Transcription Factor RelA; D051176:beta Catenin; C010770:polysaccharide-K; D005472:Fluorouracil