Membrane lipids in invadopodia and podosomes: Key structures for cancer invasion and metastasis

Yamaguchi, Hideki; Oikawa, Tsukasa

doi:10.18632/oncotarget.164

Cited by 62 publications

(28 citation statements)

References 87 publications

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“…Significantly, we found that MUC1 and CIN85 co-localize at invadopodia-like protrusions. As the invasive capacity of cancer cells depends in part on their ability to assemble invadopodia [32–35], the formation of the MUC1/CIN85 complex may be a requirement for this process. We show that MUC1 and CIN85 co-localize with two known invadopodial proteins, cortactin and MT1-MMP.…”

Section: Discussionmentioning

confidence: 99%

Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration

et al. 2013

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MUC1 is a transmembrane glycoprotein abnormally expressed in human adenocarcinomas. The extracellular domain of MUC1 contains a variable number of tandem repeats (VNTR) region that is extensively O-glycosylated in normal epithelia and underglycosylated in tumor cells. This change in posttranslational modification of MUC1 leads to changes in its normal functions including, we hypothesized, its interaction with other molecules. We identified CIN85, an adaptor protein involved in multiple cellular processes including signal transduction, cytoskeletal remodeling and cancer cell invasion, as one of several proteins that associate with MUC1 in tumor cells. CIN85 associates with both the cytosolic tail and the extracellular VNTR of MUC1. Co-immunoprecipitation and confocal immunofluorescence confirmed that MUC1 and CIN85 co-localize primarily at the plasma membrane but the complex can be found also in the cytosol and on the cytoskeleton. MUC1 and CIN85 are both over-expressed in early as well as advanced clinical stages of breast cancer and co-localize on invadopodia-like structures implicated in cell invasion. siRNA-mediated silencing of CIN85 and/or MUC1 revealed that MUC1 enhances CIN85-dependent breast cancer cell migration and invasion in vitro. However, ectopic expression of MUC1 enhances the motility induced by CIN85. When tested in vivo in a tumor metastasis model of B16 melanoma, mice injected with CIN85-depleted melanoma cells exhibited few or no lung metastasis and, similarly to the in vitro results, overexpression of MUC1 recovered the shCIN85-reduced metastatic process. Our findings implicate this newly identified CIN85/MUC1 complex associated with invadopodia-related molecules in promoting the invasive and metastatic potential of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration

et al. 2013

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“…Arp2 and Arp3 expression in cancer cells was cytoplasmic as has been previously described [12] Both proteins were co-expressed in 78 cases (88.6%) and the statistical significant correlation between Arp2 and Arp3 expression seen in positive cases suggests formation of the Arp2/3 complex in those cells [12] [13] [15]. Formation of Arp2/3 complex is a prerequisite for the neoplastic cells to form filopodia, lamellipodia and invadopodia and acquire motility [4] [5] [22] and cells that express the Arp2/3 complex have greater ability for tissue movement [8] [22] [23] [24] [25]. Similar expression of Arp2/3 complex has been reported in gastric, colorectal, breast, lung, pancreatic and liver metastasis from colon carcinomas, as well as in gliomas [12]- [18].…”

Section: Discussionmentioning

confidence: 83%

Arp2/3 Complex Is Expressed in Oral Squamous Cell Carcinoma: An Immunohistochemical Study of 88 Cases

Georgopoulou¹,

Tosios²,

Goutas³

et al. 2019

OJST

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Background: We investigated the immunohistochemical expression of Arp2/3 complex in 88 oral squamous cell carcinomas (OSCCs) and correlated it with the tumor type and grade. Materials and methods: This is a retrospective study of 88 cases of OSCCs (9 verrucous carcinomas, 4 carcinomas in situ, 37 well differentiated OSCCs, 32 moderately differentiated OSCCs, and 6 poorly differentiated OSCCs), stained with mouse monoclonal antibodies for Arp2 and Arp3. Staining was graded according to the extent of positivity by two observers. Results: Arp2 positivity was seen in 79 (89.77%) cases and Arp3 positivity in 78 (88.63%) cases. In positive cases, Arp2 expression was graded as (+) in 12.5%, (++) in 28.4% and (+++) in 48.86% of the cases; Arp3 was graded as (+) in 36.36%, (++) in 30.68% and (+++) in 21.59% of the cases. Conclusion: Expression of Arp2 and Arp3, indicative of the formation of the Arp2/3 complex, was seen in most OSCCs examined. Although no statistically significant correlation was found between the immunohistochemical expression of Arp2/Arp3 and tumor type or grade, the more common expression in invasive OSCCs than in non-invasive verrucous carcinomas and carcinomas in situ is indicative of its involvement in the biological behaviour of the lesions.The availability of Arp2/3 inhibitors that could be used in clinical practice warrants further study of the expression of Arp2/3 in OSCC.

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“…Although podosomes may play an important role in matrix remodeling during cancer metastasis, the mechanism of podosomes assembly is still unknown. 39 Microvascular endothelial cells can form podosomes without specific stimulation. 6 Nck1 has been implicated in invadopodia formation and matrix degradation in various tumor cells, including breast carcinoma and melanoma cells.…”

Section: Nck Adaptors Play An Essential Role In Podosome-mediated Mmentioning

confidence: 99%

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

2019

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BackgroundPodosomes are membrane‐bound adhesive structures formed by actin remodeling. They are capable of extracellular matrix (ECM) degradation, which is a prerequisite for cancer cell invasion and metastasis. The signaling mechanism of podosome formation is still unknown in cancer. We previously reported that Nck adaptors regulate directional cell migration and endothelial lumen formation by actin remodeling, while deficiency of Nck reduces cancer metastasis. This study evaluated the role of Nck adaptors in podosome biogenesis and cancer invasion.MethodsThis study was conducted in vitro using both healthy cells (Human Umbilical Vein Endothelial Cell, 3T3 fibroblasts) and cancer cells (prostate cancer cell line; PC3, breast cancer cell line; MDA‐MB‐231). Confocal and TIRF imaging of cells expressing Green Fluorescence Protein (GFP) mutant under altered levels of Nck or downstream of kinase 1 (Dok1) was used to evaluate the podosome formation and fluorescent gelatin matrix degradation. Levels of Nck in human breast carcinoma tissue sections were detected by immune histochemistry using Nck polyclonal antibody. Biochemical interaction of Nck/Dok1 was detected in podosome forming cells using immune precipitation and far‐western blotting.ResultsThis study demonstrates that ectopic expression of Nck1 and Nck2 can induce the endothelial podosome formation in vitro. Nck silencing by short‐hairpin RNA blocked podosome biogenesis and ECM degradation in cSrc‐Y530F transformed endothelial cells in this study. Immunohistochemical analysis revealed the Nck overexpression in human breast carcinoma tissue sections. Immunoprecipitation and far‐western blotting revealed the biochemical interaction of Nck/p62Dok in podosome forming cells.ConclusionsNck adaptors in interaction with Dok1 induce podosome biogenesis and ECM degradation facilitating cancer cell invasion, and therefore a bona fide target of cancer therapy.

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Membrane lipids in invadopodia and podosomes: Key structures for cancer invasion and metastasis

Cited by 62 publications

References 87 publications

Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration

Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration

Arp2/3 Complex Is Expressed in Oral Squamous Cell Carcinoma: An Immunohistochemical Study of 88 Cases

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

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