Human pancreatic stellate cells modulate 3D collagen alignment to promote the migration of pancreatic ductal adenocarcinoma cells

Drifka, Cole R.; Loeffler, Agnes G.; Esquibel, Corinne R.; Weber, Sharon M.; Eliceiri, Kevin W.; Kao, Weiyuan John

doi:10.1007/s10544-016-0128-1

Cited by 39 publications

(28 citation statements)

References 108 publications

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“…An additional explanation is that within αSMA + myofibroblast are present subsets of cells with different functional behaviors, with either positive or negative effects on tumor cell growth. After depletion of all αSMA + myofibroblast, these populations are lost and PDAC can grow without any brake ( 168 , 173 , 175 , 177 , 183 ). In such TME, immune system can receive misleading information with conflicting, undesired outcomes.…”

Section: Can Msc Counteract Cancer Development and Growth?mentioning

confidence: 99%

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

2018

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Experimental evidence indicates that mesenchymal stromal cells (MSCs) may regulate tumor microenvironment (TME). It is conceivable that the interaction with MSC can influence neoplastic cell functional behavior, remodeling TME and generating a tumor cell niche that supports tissue neovascularization, tumor invasion and metastasization. In addition, MSC can release transforming growth factor-beta that is involved in the epithelial–mesenchymal transition of carcinoma cells; this transition is essential to give rise to aggressive tumor cells and favor cancer progression. Also, MSC can both affect the anti-tumor immune response and limit drug availability surrounding tumor cells, thus creating a sort of barrier. This mechanism, in principle, should limit tumor expansion but, on the contrary, often leads to the impairment of the immune system-mediated recognition of tumor cells. Furthermore, the cross-talk between MSC and anti-tumor lymphocytes of the innate and adaptive arms of the immune system strongly drives TME to become immunosuppressive. Indeed, MSC can trigger the generation of several types of regulatory cells which block immune response and eventually impair the elimination of tumor cells. Based on these considerations, it should be possible to favor the anti-tumor immune response acting on TME. First, we will review the molecular mechanisms involved in MSC-mediated regulation of immune response. Second, we will focus on the experimental data supporting that it is possible to convert TME from immunosuppressive to immunostimulant, specifically targeting MSC.

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Section: Can Msc Counteract Cancer Development and Growth?mentioning

confidence: 99%

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

2018

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“…Cancer cells can also remodel collagen fibers during the process of migration. 4,8 This can either act to change mechanical properties close to the cell 23 or locally disorganize or organize collagen fibers, thus amplifying 2,14 or dampening the original aligned collagen fiber signal. This results in different degrees of contact guidance and different invasion or metastasis rates.…”

Section: Discussionmentioning

confidence: 99%

Degradation and Remodeling of Epitaxially Grown Collagen Fibrils

et al. 2018

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Introduction— The extracellular matrix (ECM) in the tumor microenvironment contains high densities of collagen that are highly aligned, resulting in directional migration called contact guidance that facilitates efficient migration out of the tumor. Cancer cells can remodel the ECM through traction force controlled by myosin contractility or proteolytic activity controlled by matrix metalloproteinase (MMP) activity, leading to either enhanced or diminished contact guidance. Methods— Recently, we have leveraged the ability of mica to epitaxially grow aligned collagen fibrils in order to assess contact guidance. In this article, we probe the mechanisms of remodeling of aligned collagen fibrils on mica by breast cancer cells. Results— We show that cells that contact guide with high fidelity (MDA-MB-231 cells) exert more force on the underlying collagen fibrils than do cells that contact guide with low fidelity (MTLn3 cells). These high traction cells (MDA-MB-231 cells) remodel collagen fibrils over hours, pulling so hard that the collagen fibrils detach from the surface, effectively delaminating the entire contact guidance cue. Myosin or MMP inhibition decreases this effect. Interestingly, blocking MMP appears to increase the alignment of cells on these substrates, potentially allowing the alignment through myosin contractility to be uninhibited. Finally, amplification or dampening of contact guidance with respect to a particular collagen fibril organization is seen under different conditions. Conclusions— Both myosin II contractility and MMP activity allow MDA-MB-231 cells to remodel and eventually destroy epitaxially grown aligned collagen fibrils.

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“…Recently, the role of PSCs in ECM remodelling is gaining attention. Using an in vitro 3D spheroid tumour model and advanced imaging techniques, Drifka et al (115) demonstrated the permissive role of PSCs in fashioning the alignment of collagen fibres to facilitate the invasion and co-migration of cancer cells through the stroma. Similarly, Sada et al (116) also using a 3D culture setting, have reported that PSCs, in response to hypoxia, reorganised collagen fibres to a parallel alignment facilitating cancer cell migration.…”

Section: Interactions Of Pscs With Other Cells In the Stromamentioning

confidence: 99%

Multifunctional role of pancreatic stellate cells in pancreatic cancer

Mekapogu¹,

Pothula²,

Pirola³

et al. 2019

Ann Pancreat Cancer

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Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of all pancreatic malignancies and is characterised by extensive desmoplasia and early metastasis. The risk factors for PDAC include a family history of the disease, cigarette smoking, chronic pancreatitis, obesity and diabetes mellitus (1,2). PDAC most commonly occurs in the 60 to 80 year age group, and its incidence is 50% higher in men than in women and (1) genetic mutations such as BRCA2, CDKN2A, STK11, PRSS1, SPINK1, CFTR, PALB2 and ATM increase the risk for PDAC (3), patients with chronic pancreatitis have a 15 fold increased risk of developing PDAC (4), cigarette smoking increases the risk of PDAC by 75% even up to 10 years after cessation of smoking and (5) diabetes mellitus increases the risk by 30% up to 20 years after diagnosis (6). Obesity and high body mass index are positively correlated with the risk of developing PDAC (7). One meta-analysis showed a 19% increase in risk of developing PDAC in obese individuals (BMI ≥30 kg/m 2) compared to normal participants (BMI 22 kg/m 2) (8). The genetic mutational landscape of PDAC involves the alteration of 69 genes which affect 12 core signalling pathways (9). Both oncogenes and tumour suppressor genes are mutated of which the major genes involved in PDAC are the oncogene Kristen Rat Sarcoma Virus (KRAS), and three tumour suppressor genes-TP53, CDKN2A and SMAD4. KRAS is the earliest mutation seen in low-grade pancreatic

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Human pancreatic stellate cells modulate 3D collagen alignment to promote the migration of pancreatic ductal adenocarcinoma cells

Cited by 39 publications

References 108 publications

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

Degradation and Remodeling of Epitaxially Grown Collagen Fibrils

Multifunctional role of pancreatic stellate cells in pancreatic cancer

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