From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

Kaushik, Shelly; Pickup, Michael W.; Weaver, Valerie M.

doi:10.1007/s10555-016-9650-0

Cited by 133 publications

(115 citation statements)

References 126 publications

(156 reference statements)

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“…HCC1937 cells were chosen because they showed a clear response in the earlier experiments and are derived from a primary tumour and so represent pre-metastatic cells [ 28 ]. This was of particular interest as modifications to the ECM at the primary site are widely regarded as essential for metastasis initiation [ 51 , 52 ]. ECM from HCC1937 was highly supportive of attachment and spreading of HCC1937 cells.…”

Section: Discussionmentioning

confidence: 99%

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

et al. 2020

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Protein disulphide isomerase A3 (PDIA3) is an ER-resident disulphide isomerase and oxidoreductase with known substrates that include some extracellular matrix proteins. PDIA3 is upregulated in invasive breast cancers and correlates in a mouse orthotopic xenograft model with breast cancer metastasis to bone. However, the underlying cellular mechanisms remain unclear. Here we investigated the function of protein disulphide isomerases in attachment, spreading and migration of three human breast cancer lines representative of luminal (MCF-7) or basal (MDA-MB-231 and HCC1937) tumour phenotypes. Pharmacological inhibition by 16F16 in cells decreased initial cell spreading more effectively than inhibition by PACMA-31. Cells displayed diminished cortical F-actin projections, stress fibres and focal adhesions. Cell migration was reduced in a quantified “scratch wound” assay. To examine whether these effects might result from alterations to secreted proteins in the absence of functional PDIA3, adhesion and migration were quantified in the above cells exposed to media conditioned by wild-type or Pdia3-/- mouse embryo fibroblasts. The conditioned medium of Pdia3-/- fibroblasts was less effective in promoting cell spreading and F-actin organisation or supporting “scratch wound” closure. Similarly, extracellular matrix prepared from HCC1937 cells after 16F16 inhibition was less effective than control ECM to support spreading of untreated HCC1937 cells. Overall, these results advance the concept that protein disulphide isomerases including PDIA3 drive the production of secreted proteins that promote a microenvironment favourable to breast cancer cell adhesion and motility, characteristics that are integral to tumour invasion and metastasis. Inhibition of PDIA3 or related isomerases may have potential for anti-metastatic therapies.

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Section: Discussionmentioning

confidence: 99%

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

et al. 2020

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“…Matrix stiffness in TMEs mechanistically is another mechanical cause for hypoxia-induced tumor metastasis [242]. Matrix stiffness can be made stiffer upon cross-linkages among collagen fibers by LOX, one of products secreted by tumor cells that are under hypoxic conditions [243][244][245].…”

Section: Hypoxia-induced Reexpression Of Fn In Tumor Cells and Cancermentioning

confidence: 99%

Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

147

117

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The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Figure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). On the contrary, Among 46 publications after 2000, 7 (15.2%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 25 (54.4%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 14 (30.4%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). Abbreviations in boxes are referred to the context of this article. (C) Percentages of articles for the three various roles of FN (the same colors as depicted in (B) before 2000 and after 2000. Numbers in the parenthesis represent article numbers. The Pathobiology of CancerFigure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the r...

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“…This occurs not only by providing optimal contractile forces for the migration of tumor cells, but also by affecting signaling (mechanotransduction), which can alter growth and even responses to drugs. Work from the Weaver laboratory and others has shown that in the breast cancer setting, increasing stiffness of the ECM can drive increased metastasis and resistance to chemotherapy through different processes as reviewed elsewhere (Kaushik, Pickup, & Weaver, ). Surprisingly, and in contrast to existing studies in other cancers, recent modeling experiments from our own laboratory suggest that this may be different in melanoma.…”

Section: The Stromal Microenvironment In Resistance To Mapk Blockadementioning

confidence: 99%

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

Almeida

Douglass

Fane

et al. 2018

Pigment Cell Melanoma Res

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This review will focus on the role of the tumor microenvironment (TME) in the development of drug resistance in melanoma. Resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma is observed months after treatment, a phenomenon that is often attributed to the incredible plasticity of melanoma cells but may also depend on the TME. The TME is unique in its cellular composition-it contains fibroblasts, immune cells, endothelial cells, adipocytes, and among others. In addition, the TME provides "non-homeostatic" levels of oxygen, nutrients (hypoxia and metabolic stress), and extracellular matrix proteins, creating a pro-tumorigenic niche that drives resistance to MAPKi treatment. In this review, we will focus on how changes in the tumor microenvironment regulate MAPKi resistance.

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From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

Cited by 133 publications

References 126 publications

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

Impairment of cell adhesion and migration by inhibition of protein disulphide isomerases in three breast cancer cell lines

Fibronectin in Cancer: Friend or Foe

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

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