Molecular Mechanisms of Cancer Invasion and Metastasis

in Japanese

Metastasis is one of the major obstacles to the treatment of any cancer. Surgical management of cancer with no lymph node or organ metastasis is generally uncomplicated, but the treatment of metastatic disease remains challenging. Acquisition of increased motility by cancer cells seems to be a requirement for cancer invasion and metastasis, and during the process of cell movement, the actin cytoskeleton is dynamically remodeled by the functions of various classes of actin-binding proteins.

Identification of actinin-4 as a biomarker of cancer invasion and an indicator of prognosis for cancer patients
Actinin-4 was identified in our laboratory as a novel actin-binding protein associated with increased cell motility and cancer invasion (1). Breast cancer(PDF:27KB) patients with cytoplasmic and/or cell membrane localization of actinin-4 were found to have a poorer outcome than breast cancer patients with nuclear localization. Actinin-4 expression has also been found to be significantly correlated with the outcome of colorectal(PDF:27KB) (2), ovarian (3), and pancreatic cancer patients (4). In addition, gene amplification of ACTN4 was observed in ovarian (5) and pancreatic cancers (4). We have found that an increase in DNA copy number of ACTN4 seems to predict poor prognosis in patients with high-grade ovarian carcinomas(PDF:23KB) (5).

Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer
Overexpression of actinin-4 promoted the formation of cellular protrusions(PDF:27KB) and cell motility (2). When actinin-4-expressing colorectal cancer cells were injected into the mesocecum of severe combined immunodeficient (SCID) mice, they metastasized to regional mesenteric lymph nodes(PDF:27KB) in a manner resembling the behavior of clinical cancers (2).

E-cadherin regulates the association between β-catenin and actinin-4
The E-cadherin/catenin system acts as an invasion suppressor of various epithelial malignancies. However, loss of cell adhesion is insufficient to explain its full invasion suppressive activity, and involvement of some β-catenin-binding protein has been speculated. We searched for the molecule linking E-cadherin/catenin to cell motility by a proteomic approach and were surprised to discover that it was actinin-4. Immunofluorescence histochemistry(PDF:27KB) of colorectal cancer specimens showed that the -catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma (6).

References
1. Honda et al., J Cell Biol 140:1383-1393, 1998.
2. Honda et al., Gastroenterology 128:51-62, 2005
3. Yamamoto et al., Mod Pathol 20:1278-1285, 2007.
4. Kikuchi et al., Clin Cancer Res 14:5348-5356, 2008
5. Yamamoto et al., Mod Pathol 22:499-507, 2009.
6. Hayashida et al., Cancer Res 65:8836-8845, 2005.
7. Honda et al., Oncogene 23:5257-5262, 2004.
8. Hara et al., Mol Cell Proteomics 6:479-491, 2007.
9. Honda et al., Seikagaku 79:643-54, 2007.

to this page top