Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

Calvé, Benjamin Le; Griveau, Audrey; Vindrieux, David; Maréchal, Raphaël; Wiel, Clotilde; Svrcek, Magali; Gout, Johann; Azzi, Lamia; Payen, Léa; Cros, Jérôme; Fouchardière, Christelle De La; Dubus, Pierre; Guitton, Jérôme; Bartholin, Laurent; Bachet, Jean‐Baptiste; Bernard, David

doi:10.18632/oncotarget.8527

Cited by 64 publications

(63 citation statements)

References 39 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the increased expression of ECM proteins in tumor biopsies could be from both cancer cells and stromal cells known to be present in tumors. Several studies have shown that cancer-associated fibroblasts and macrophages synthesise increased levels of ECM proteins and these ECM proteins are associated with poor prognosis and chemoresistance in several cancer types [ 18 , 79 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ]. Our data is in agreement with these recent studies illustrating the important role the ECM plays in the tumor microenvironment and in chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Senthebane

Jonker

Rowe

et al. 2018

IJMS

109

176

View full text Add to dashboard Cite

Background: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments. Methods: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM; cancer cell-derived ECM; combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µM cisplatin, 3.5 µM 5-fluorouracil and 2.5 µM epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints. Results: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20–60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30–50%, and reduced colony formation and cancer cell migration. Conclusion: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

Senthebane

Jonker

Rowe

et al. 2018

IJMS

109

176

View full text Add to dashboard Cite

show abstract

“…In addition, supply-limiting effects were observed in systems—MCTS and non-vascularized metastases—in which vascular effects can be excluded. In contrast, Le Calve et al reported a strong increase in vascular collapse after LOXL2 application, which they considered causal for reduced drug supply and response [ 18 ]. The fact that they applied LOXL2 by systemic injection rather than by ectopic overexpression in situ might explain why their results are in conflict with other findings.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been shown that the high water content of hyaluronan-rich pancrease tumors creates a high interstitial pressure, interfering with drug distribution [ 16 , 17 ]. Likewise, high fibrillar collagen deposition might lead to vascular collapse subsequently obstructing drug supply [ 18 ]. Finally, the distribution of therapeutic antibodies is strongly restricted by the ECM [ 2 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy

et al. 2018

View full text Add to dashboard Cite

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.

show abstract

“…MRP-1 and P-gp, located at the membrane of cancer cells, could pump chemotherapeutic drugs out via endoergic reaction ( 40 , 41 ). Recent study has demonstrated that LOXL2 can inhibit the diffusion of gemcitabine in the pancreatic ductal adenocarcinoma (PDAC) ( 42 ). Survivin ( 43 ), Livin ( 44 ) and Bcl-2 could enhance the anti-apoptosis of cancer cells, while in contrast Bax can promote apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Salidroside could enhance the cytotoxic effect of L‑OHP on colorectal cancer cells

et al. 2017

View full text Add to dashboard Cite

Evidence has suggested that salidroside inhibits the proliferation and invasion of renal clear cell, lung, breast, and colon cancer. However, effect of salidroside on colorectal cancer (CRC) cells against oxaliplatin (L-OHP) resistance remains unclear. In the present study, the CRC HT-29 cell line and L-OHP resistance HT-29/L-OHP cell line were used to evaluate the effect, and mechanism of salidroside on L-OHP resistance. The results demonstrated that the activity of HT-29 cells was lower compared with that of HT-29/L-OHP cells following L-OHP intervention, and was accompanied with varied expression levels of drug resistant proteins. The combination of salidroside and L-OHP weakened cell activity significantly compared single utilization. Compared with the control group, salidroside intervention resulted in a higher percentage of HT-29/L-OHP cells in the G0/G1 stage, and reduced percentage in the G2/M stage, but no significant variation in the S stage. The HT-29/L-OHP cells exhibited increased apoptosis rates and caspase-3 activity, but decreased metastatic, and invasive abilities following salidroside intervention. Quantitative polymerase chain reaction and western blot analysis detected variations in the expression levels of associated genes in HT-29/L-OHP cells following salidroside intervention. In all, the results of the present study revealed that salidroside is able to decrease the activity and invasive capacity of HT-29/L-OHP cells, and treatment with salidroside is associated with increased apoptosis of cancer cells through the regulation of certain genes.

show abstract

Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution

Cited by 64 publications

References 39 publications

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices

LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy

Salidroside could enhance the cytotoxic effect of L‑OHP on colorectal cancer cells

Contact Info

Product

Resources

About