Development of Biomarkers to Predict Recurrence by Determining the Metastatic Ability of Cancer Cells

Abstract

Adjuvant chemotherapy has been carried out for patients with cancer who underwent curative resection, but it is basically not needed for patients without micro-metastatic lesions who undergo a perfectly curative surgical operation. The patients who need adjuvant chemotherapy are defined as those whose micrometastases cannot be detected by imaging modalities in the other sites of the resective areas, despite curative resection for the primary sites. If biomarkers to efficiently evaluate the metastatic potential of each patient could be developed, we may be able to provide personalized adjuvant chemotherapy in the clinical setting. Actinin-4 (ACTN4, gene name ACTN4) is an actin-bundling protein that we identified in 1998 as a novel molecule involved in cancer invasion and metastasis. Protein overexpression of actinin-4 in cancer cells leads to the invasive phenotype, and patients with gene amplification of ACTN4 have a worse prognosis than patients with a normal copy number in some cancers, including pancreas, lung, and salivary gland cancers. In this review, the biological roles of actinin-4 for cancer invasion and metastasis are summarized, and the potential usefulness of actinin-4 as a biomarker for evaluation of metastatic ability is examined.

Copy number gain of ACTN4 is associated with poor prognosis in patients with upper urinary tract urothelial carcinoma

“…ACTN4, an actin crosslinking protein, plays a role in regulating cell motility and invasiveness 5–7 . Its molecular aberration has been known to be correlated with aggressiveness, invasion, and metastasis of certain tumors 5,9–26 .…”

“…ACTN4, an actin crosslinking protein, plays a role in regulating cell motility and invasiveness. 5 , 6 , 7 Its molecular aberration has been known to be correlated with aggressiveness, invasion, and metastasis of certain tumors. 5 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 In the present study, protein overexpression of ACTN4 and copy number gain of ACTN4 were detected in 29% and 15% of examined UUTUCs, respectively, both of which are related to several conventional pathological parameters such as pT stage, LVI, lymph node metastasis, tumor location, subtype histology, and gross findings.…”

“…ACTN4 is an isoform of non‐muscular α‐actinin, which bundles the actin cytoskeleton proteins and is involved in the enhancement of cell motility and promotion of cancer infiltration and metastasis 5,6 . ACTN4 has been shown to affect various steps of EMT that are thought to be important for the migration of epithelial cancer cells from the primary tumor to the formation of metastases in distant organs 7,8 .…”

“…ACTN4 is an isoform of non‐muscular α‐actinin, which bundles the actin cytoskeleton proteins and is involved in the enhancement of cell motility and promotion of cancer infiltration and metastasis. 5 , 6 ACTN4 has been shown to affect various steps of EMT that are thought to be important for the migration of epithelial cancer cells from the primary tumor to the formation of metastases in distant organs. 7 , 8 Increased ACTN4 protein expression or ACTN4 gene (located on chromosome 19q14) expression has been reported to be associated with the recurrence and metastasis in various carcinomas including colorectal, 9 , 10 breast, 5 , 11 , 12 lung, 13 , 14 , 15 , 16 pancreatic, 17 , 18 ovarian, 19 , 20 , 21 salivary gland, 22 oral/tongue, 23 and prostate cancers.…”

Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer: Possibility of Stratification by Gene Amplification of ACTN4 According to Evaluation of Metastatic Ability

“…Non-muscle types of alpha-actinin, including ACTN4, are related to cell adhesion and cell migration. ACTN-4 has been reported to show increased protein expression in several types of cancers, such as colorectal cancer, pancreatic cancer, ovarian cancer, oral squamous cell carcinoma [ 29 , 69 , 70 , 71 , 72 ], salivary gland carcinoma [ 73 ], and lung cancer [ 28 , 74 , 75 , 76 ]. Cancer cells at the invasive front of the primal site have high migration and metastatic ability.…”