Localization of the Invadopodia-Related Proteins Actinin-1 and Cortactin to Matrix-Contact-Side Cytoplasm of Cancer Cells in Surgically Resected Lung Adenocarcinomas

Hirooka, Shinichi; Akashi, Takumi; Ando, Noboru; Suzuki, Yoshimi; Ishida, Noriko; Kurata, Morito; Takizawa, Touichiro; Kayamori, Kou; Sakamoto, Kei; Fujiwara, Naoyuki; Kojima, Masao; Eishi, Yoshinobu

doi:10.1159/000322734

Cited by 26 publications

(19 citation statements)

References 91 publications

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“…Previous clinical studies of another invadopodia component, cortactin, indicate that its elevated expression and dysregulated cellular localization correlate with poor survival in laryngeal carcinoma and lung adenocarcinoma, respectively, underlining the relevance of invadopodia activity in predicting clinical outcomes (Gibcus et al 2008;Hirooka et al 2011). Consistent with these studies, our data show that a high level of Tks5 long expression and a low level of Tks5 short expression correlate with metastatic progression of lung adenocarcinoma patients and predict poor survival of patients with early stage disease, suggesting that the Tks5 long to Tks5 short ratio may serve as a prognostic marker for assessing the metastatic potential of primary tumors and for identifying early stage patients who bear higher risks for metastasis and may benefit from adjuvant therapy after tumor resection.…”

Section: Discussionmentioning

confidence: 99%

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Chen

Dayton

et al. 2013

Genes Dev.

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Metastasis accounts for the vast majority of cancer-related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to the formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically engineered mouse model of lung adenocarcinoma. Nonmetastatic primary tumor-derived cells predominantly expressed a short isoform, Tks5 short , while metastatic primary tumor-and metastasis-derived cells acquired increased expression of the full-length isoform Tks5 long . This elevation of Tks5 long to Tks5 short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared with nonmetastatic cells. Further characterization of these isoforms by knockdown and overexpression experiments demonstrated that Tks5 long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5 short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5 long . Importantly, high Tks5 long and low Tks5 short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5 long to Tks5 short ratio promotes invadopodia-mediated invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Chen

Dayton

et al. 2013

Genes Dev.

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“…The preparation of mRNA from A549 and normal airway epithelial cells, as well as the quantification of MT1-MMP mRNA, was similar to a previous description [11] .…”

Section: Rna Extraction and Rt-pcrmentioning

confidence: 87%

“…In contrast, in the squamous cell carcinoma A431 cells, the actomyosin filament is localized to the cell cortex in contact with extracellular matrix and it participates in collective cell migration [5] . In our previous study, subcellular localization of the actin-binding proteins actinin-1 and cortactin showed translocation from the apical side to the matrix side facing surrounding interstitium in lung cancer cells and it significantly correlated to cancer cell invasion [11] . Accordingly, we hypothesized that the subcellular translocation of F-actin possibly occurs in cancer cells and this participates in invasion.…”

mentioning

confidence: 84%

“…The scoring of immunohistochemical findings was done on paraffin sections. As a proportion of positive or negative cells showed a more prominent difference among the examined cases and this was easier to quantify than the strength of staining, grading was according to the proportion of positive cells (β-actin) or negative cells (laminin-C1) [11] . The following scale was used: none as "0", up to 5% as "1", 5% to one-third as "2", one-to twothirds as "3", two-thirds to 95% as "4", 95% to less than 100% as "5", and 100% as "6".…”

Section: Immunohistochemical Examinationmentioning

confidence: 99%

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Cortical Actin Alteration at the Matrix-Side Cytoplasm in Lung Adenocarcinoma Cells and Its Significance in Invasion

Tomii¹,

Akashi²,

Ando³

et al. 2016

Pathobiology

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Objectives: Cortical actin is a thin layer of filamentous (F-)actin that lies beneath the plasma membrane, and its role in pathophysiology remains unclear. We investigated the subcellular localization of cortical actin by the histopathological and experimental studies of lung adenocarcinomas. Materials and Methods: The subcellular localization of cortical actin was studied in surgically resected lung adenocarcinomas tissues and in 3-dimensionally cultured lung adenocarcinoma A549 cells. Results: In normal type II alveolar cells and the bronchiolar epithelium, cortical actin was localized to the apical-side cytoplasm. In invasive adenocarcinoma cells, cortical actin was frequently localized to the matrix side. The degree of cortical actin localized to the matrix side was associated with the loss of basement membrane and a poor prognosis. In A549 cell spheroids cultured in a type I collagen and basement membrane extract Matrigel™ mixed gel, cortical F-actin was localized to the matrix side with phosphorylated myosin light chain. Super-resolution and electron microscopy results suggest that compact wrinkling of the plasma membrane by myosin-mediated F-actin contraction is an explanation for cortical actin accumulation at the matrix side. The myosin II inhibitor blebbistatin suppressed the 3-dimensional collective migration of A549 cells induced by constitutively active Cdc42 and MT1-MMP. Conclusion: Cortical actin accumulation at the matrix-side cytoplasm of cancer cells occurs in invasive lung adenocarcinomas and it possibly participates in the migration of cancer cells through myosin-mediated contraction.

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“…Invadopodia has been demonstrated in metastasis of different variants of lung cancers, including lung adenocarcinoma [31,32]. It is not known whether this is a general phenomenon or only restricted to certain variants.…”

Section: Discussionmentioning

confidence: 99%

Significance of Trask protein interactions in brain metastatic cohorts of lung cancers

Shang

Chen

et al. 2015

Tumor Biol.

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A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer.

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Localization of the Invadopodia-Related Proteins Actinin-1 and Cortactin to Matrix-Contact-Side Cytoplasm of Cancer Cells in Surgically Resected Lung Adenocarcinomas

Cited by 26 publications

References 91 publications

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Cortical Actin Alteration at the Matrix-Side Cytoplasm in Lung Adenocarcinoma Cells and Its Significance in Invasion

Significance of Trask protein interactions in brain metastatic cohorts of lung cancers

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