Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration

Jayatilaka, Hasini; Tyle, Pranay; Chen, Jonathan J.; Kwak, Myung-Jun; Ju, Julia A.; Kim, Hyun Ji; Lee, Jerry S.H.; Wu, Pei Hsun; Gilkes, Daniele M.; Fan, Rong; Wirtz, Denis

doi:10.1038/ncomms15584

Cited by 150 publications

(164 citation statements)

References 57 publications

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“…Similar results have been reported by Jayatilaka et al, 6 and they found that the metastatic cancer cell lines HT1080, MDA-MB-231, and U-87 acquired enhanced migration and invasion abilities due to increased cell density in 3D collagen matrices. Then, the same numbers of cells from the dense or sparse cultures were tested in proliferation, migration, and invasion assays.…”

Section: Introductionsupporting

confidence: 90%

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Proteomic analysis of the effects of cell culture density on the metastasis of breast cancer cells

Guo

Mixin

Lan

et al. 2019

Cell Biochemistry & Function

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Cancer cell progression and proliferation increase cell density, resulting in changes to the tumour site, including the microenvironment. What is not known is if increased cell density influences the aggressiveness of cancer cells, especially their proliferation, migration, and invasion capabilities. In this study, we found that dense cell culture enhances the aggressiveness of the metastatic cancer cell lines, 4T1 and ZR-75-30, by increasing their proliferation, migration, and invasion capabilities. However, a less metastatic cell line, MCF-7, did not show an increase in aggressiveness, following dense cell culture conditions. We conducted a differential proteomic analysis on 4T1 cells cultured under dense or sparse conditions and identified an increase in expression for proteins involved in migration, including focal adhesion, cytoskeletal reorganization, and transendothelial migration. In contrast, 4T1 cells grown under sparse conditions had higher expression levels for proteins involved in metabolism, including lipid and phospholipid binding, lipid and cholesterol transporter activity, and protein binding.These results suggest that the high-density tumour microenvironment can cause a change in cellular behaviour, leading towards more aggressive cancers.Significance of the study: Metastasis of cancer cells is an obstacle to the clinical treatment of cancer. We found that dense cultures made metastatic cancer cells more potent in terms of proliferation, migration, and invasion. The proteomic and bioinformatic analyses provided some valuable clues for further intensive studies about the effects of cell density on cancer cell aggressiveness, which were associated with events such as pre-mRNA splicing and RNA transport, focal adhesion and cytoskeleton reorganization, ribosome biogenesis, and transendothelial migration, or associated with proteins, such as JAM-1 and S100A11. This investigation gives us new perspectives to investigate the metastasis mechanisms related to the microenvironment of tumour sites.

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Section: Introductionsupporting

confidence: 90%

“…JAM-1 was decreased in samples from dense cultures, which was verified by a western blot. 6 IL-6 and IL-8 are two cytokines that are amplified by cell proliferation and cell density to promote cell migration directly. 24 However, it was reported that the downregulation of JAM-1 in cancer cells can lead to metastasis and poor survival.…”

Section: Figurementioning

confidence: 99%

Proteomic analysis of the effects of cell culture density on the metastasis of breast cancer cells

Guo

Mixin

Lan

et al. 2019

Cell Biochemistry & Function

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“…MMP‐9, an enzyme secreted by various tumor cells,1, 25, 26 including B16F10 cells,27, 28, 29 can degrade the extracellular matrix, facilitate detachment and invasion, and enhance tumor cells entry into blood vessels. Thus, TOS can inhibit the beginning of the metastatic cascade, which is a crucial stage of metastasis 30. Based on the above, we constructed a simple self‐delivering micellar NP consisting of the antimetastatic components LMWH and TOS, which inhibit different phases of the metastatic cascade ( Scheme 1 C).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Melanoma‐Targeted Therapy by “Fru‐Blocked” Phenyboronic Acid‐Modified Multiphase Antimetastatic Micellar Nanoparticles

Long

Mei

et al. 2018

Advanced Science

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Metastasis remains the main driver of mortality in patients suffering from cancer because of the refractoriness resulting from the multi‐phase metastatic cascade. Herein, a multifunctional self‐delivering PBA‐LMWH‐TOS nanoparticle (PLT NP) is established that acts as both nanocarrier and anti‐metastatic agent with effects on most hematogenous metastases of cancers. The hydrophilic segment (low molecular weight heparin, LMWH) inhibits the interactions between tumor cells and platelets. The hydrophobic segment (d‐α‐tocopheryl succinate, TOS) could inhibit the expression of matrix metalloproteinase‐9 (MMP‐9) in B16F10 cells which is first reported in this article. Surprisingly, even the blank NPs showed excellent anti‐metastatic capacity in three mouse models by acting on different phases of the metastatic cascade. Moreover, the overexpression of sialic acid (SA) residues on tumor cells is implicated in the malignant and metastatic phenotypes of cancers. Thus, these 3‐aminophenylboronic acid (PBA)‐modified doxorubicin (DOX)‐loaded NPs offer an efficient approach for the treatment of both solid melanomas and metastases. Furthermore, a simple pH‐sensitive “Fructose (Fru)‐blocking” coping strategy is established to reduce the NP distribution in normal tissues and distinctly increases the accumulation in melanoma tumors. These micellar NPs consisting of biocompatible materials offer a promising approach for the clinical therapy of highly invasive solid tumors and metastases.

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“…Recent studies have shown that the key proteins and organelles that play a critical role in conventional 2D migration do not necessarily play a significant role in 3D migration and vice versa. For instance, the Arp2/3 complex-based module for dendritic assembly of F-actin and the associated regulatory/activator proteins such as N-WASP and Cdc42 have remarkably different effects on cell migration in 2-and 3D environments (5,10). Similarly, focal adhesion proteins, such as vinculin and p130Cas, play critical roles in 3D migration that are not necessarily predicted by the 2D case (5,11,12).…”

mentioning

confidence: 99%

EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3‐dimensional cell migration

et al. 2018

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Microtubules have long been implicated to play an integral role in metastatic disease, for which a critical step is the local invasion of tumor cells into the 3-dimensional (3D) collagen-rich stromal matrix. Here we show that cell migration of human cancer cells uses the dynamic formation of highly branched protrusions that are composed of a microtubule core surrounded by cortical actin, a cytoskeletal organization that is absent in cells on 2-dimensional (2D) substrates. Microtubule plus-end tracking protein End-binding 1 and motor protein dynein subunits light intermediate chain 2 and heavy chain 1, which do not regulate 2D migration, critically modulate 3D migration by affecting RhoA and thus regulate protrusion branching through differential assembly dynamics of microtubules. An important consequence of this observation is that the commonly used cancer drug paclitaxel is 100-fold more effective at blocking migration in a 3D matrix than on a 2D matrix. This work reveals the central role that microtubule dynamics plays in powering cell migration in a more pathologically relevant setting and suggests further testing of therapeutics targeting microtubules to mitigate migration.—Jayatilaka, H., Giri, A., Karl, M., Aifuwa, I., Trenton, N. J., Phillip, J. M., Khatau, S., Wirtz, D. EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3-dimensional cell migration.

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Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration

Cited by 150 publications

References 57 publications

Proteomic analysis of the effects of cell culture density on the metastasis of breast cancer cells

Proteomic analysis of the effects of cell culture density on the metastasis of breast cancer cells

Enhanced Melanoma‐Targeted Therapy by “Fru‐Blocked” Phenyboronic Acid‐Modified Multiphase Antimetastatic Micellar Nanoparticles

EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3‐dimensional cell migration

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