Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis

Dong, Youhai; Zheng, Qin; Wang, Zhiming; Lin, Xiahui; You, Yang; Wu, Sheng; Wang, Yaohui; Hu, Chao; Xie, Xiaoying; Chen, Jie; Gao, Dongmei; Zhao, Yan; Wu, Wei‐Zhong; Liu, Yinkun; Ren, Zhenggang; Chen, Rongxin; Cui, Jiefeng

doi:10.1186/s13045-019-0795-5

Cited by 133 publications

(131 citation statements)

References 49 publications

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“…Targeting hypoxia has thus been suggested to improve the efficacy of cancer immunotherapy [102,104,105] . Remodeling of ECM through secretion of specific matrix MMPs and new ECM components, namely collagen type 1, has been shown to induce EMT through both mechanotransduction and direct membrane receptor signaling through integrins and DDR1/2 [106][107][108] . Cancer-associated fibroblasts (CAFs), in addition to their role in ECM remodeling, serve as one of the primary sources of key EMT-inducing growth factors including hepatocyte growth factor (HGF), fibroblast growth factor, interleukin (IL)-6 and transforming growth factor-beta (TGF-β); however, molecular profiling and ablation of heterogeneous CAF subsets in various tumor models have shown conflicting and context-dependent effects on the efficacy of different therapies [109] .…”

Section: The Tumor Immune Microenvironment As a Regulator Of Epithelimentioning

confidence: 99%

Decoding cancer’s camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

Lotsberg¹,

Rayford²,

Thiery³

et al. 2020

CDR

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Epithelial-mesenchymal plasticity (EMP) of cancer cells contributes to cancer cell heterogeneity, and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy, chemotherapy, and targeted therapies. Here, we aimed to explore how EMP contributes to cancer cell camouflage, allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies. The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment. The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated, particularly for the spectrum of collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions. This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells. Therapeutic strategies currently in clinical development will be discussed.

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Section: The Tumor Immune Microenvironment As a Regulator Of Epithelimentioning

confidence: 99%

Decoding cancer’s camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

Lotsberg¹,

Rayford²,

Thiery³

et al. 2020

CDR

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“…LOXL2 modulates matrix rigidity, increasing collagen crosslinking and promoting invasion ( 149 ). Matrix accumulation and crosslinking increase stiffness, inducing HCC cell proliferation and invasion ( 150 ). Physical parameters seem to be crucial to promote HCC progression.…”

Section: Liver Cancermentioning

confidence: 99%

A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression

2020

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Tumor microenvironment, including extracellular matrix (ECM) and stromal cells, is a key player during tumor development, from initiation, growth and progression to metastasis. During all of these steps, remodeling of matrix components occurs, changing its biochemical and physical properties. The global and basic cancer ECM model is that tumors are surrounded by activated stromal cells, that remodel physiological ECM to evolve into a stiffer and more crosslinked ECM than in normal conditions, thereby increasing invasive capacities of cancer cells. In this review, we show that this too simple model does not consider the complexity, specificity and heterogeneity of each organ and tumor. First, we describe the general ECM in context of cancer. Then, we go through five invasive and most frequent cancers from different origins (breast, liver, pancreas, colon, and skin), and show that each cancer has its own specific matrix, with different stromal cells, ECM components, biochemical properties and activated signaling pathways. Furthermore, in these five cancers, we describe the dual role of tumor ECM: as a protective barrier against tumor cell proliferation and invasion, and as a major player in tumor progression. Indeed, crosstalk between tumor and stromal cells induce changes in matrix organization by remodeling ECM through invadosome formation in order to degrade it, promoting tumor progression and cell invasion. To sum up, in this review, we highlight the specificities of matrix composition in five cancers and the necessity not to consider the ECM as one general and simple entity, but one complex, dynamic and specific entity for each cancer type and subtype.

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“…The detailed procedure of immunohistochemistry sees our previous work [25]. Tissue slides were separately incubated with the diluted primary antibody against LOXL2 (1:200, Novus), Fibronectin (1:100, Proteintech), Collagen I (1:200, A nity), LOX (1:100, Abcam) at 4℃ overnight, and then reacted with the diluted secondary antibody(?).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Increased matrix stiffness is a remarkable physical property of Hepatocellular carcinoma (HCC) and its clinical signi cance has been highlighted in prediction of HCC progression and prognosis [19][20][21]. Other studies in vitro also suggest that higher matrix stiffness strengthens malignant characteristics of HCC cells and facilitates HCC invasion and metastasis by upregulating invasion/metastasis-associated gene expression [22,23], enhancing stemness characteristics [24], triggering the occurrence of epithelial-mesenchymal transition [25,26], promoting therapeutic resistance [27]. However, little effort has been dedicated to exploring the relationship between matrix stiffness and pre-metastatic niche in HCC.…”

Section: Introductionmentioning

confidence: 99%

The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism

Xing

Wang

et al. 2020

Preprint

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Background: The mechanisms underlying the contribution of primary tumor to pre-metastatic niche formation remains largely unknown in HCC. We previously reported that the released Lysyl oxidase like 2 (LOXL2) from HCC cells under higher stiffness stimulation facilitated the formation of lung pre-metastatic niche. Here we further clarified the pathological role of LOXL2 in promoting lung pre-metastatic niche formation in HCC and its relevant molecular mechanism. Methods: Lung pre-metastatic niche nude mouse model and LOXL2-overexpressed xenograft HCC models were respectively developed to validate the significance of LOXL2 in pre-metastatic niche formation and pulmonary metastasis. Simultaneously, a gel-based cell culture system mirroring lung tissue stiffness in normal and pathological state was constructed to investigate the underlying mechanism of LOXL2-induced pre-metastatic niche formation.Results: LOXL2 by tail vein injection had obvious inducting effects on CD11b+/CD45+ BMDCs recruitment and fibronectin expression in lung tissue during the development of lung pre-metastatic niche. Tumor-secreted LOXL2 also promoted the occurrence of pulmonary metastasis and the number of metastasis lesions remarkably in LOXL2-overexpressed xenograft HCC models. Applying a gel-based cell culture system, we discovered that LOXL2 and LOXL2-caused matrix stiffening all upregulated the expressions of MMP9 and fibronectin in lung fibroblasts significantly, but little effect on MMP2 expression. Moreover, the activation of PI3K-AKT pathway participated in the regulation of LOXL2-upregulated fibronectin. Additionally, LOXL2 and LOXL2-caused matrix stiffening also increased the number of adherent HCC cells evidently, as well as the expression of chemokine CXCL2. Clinical data analysis demonstrated that HCC patients in High-LOXL2 group had higher ratio of microvascular invasion (OR=10.563, P=0.005) and tumor recurrence (OR=8.556, P=0.013) than HCC patients in Low-LOXL2 group, also revealing a significance of LOXL2 in HCC progression and unfavorable outcomeConclusion: Primary tumor-released LOXL2 contributes to the formation of lung pre-metastatic niche and the occurrence of lung metastasis. LOXL2 and LOXL2-caused matrix stiffening work together to induce pre-metastatic niche formation through influencing matrix remodeling and cell colonization. This study sheds light on the pathological significance of LOXL2 in lung pre-metastatic niche formation in HCC, also implicates a new intervention approach for HCC metastasis through reversal of lung pre-metastatic niche.

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Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis

Cited by 133 publications

References 49 publications

Decoding cancer’s camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

Decoding cancer’s camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade

A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression

The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism

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