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Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts.

ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1) promotes pulmonary fibrosis through increasing myofibroblast (MF) characteristics, expressing alpha-smooth muscle actin (α-SMA) in fibroblasts. Fibroblasts in the tumour stroma are called cancer-associated fibroblasts (CAFs). Some CAFs have MF characteristics and substantially promote tumour progression and chemotherapy resistance. This study determined whether inhibition of PAI-1 suppressed MF characteristics of CAFs and limited chemotherapy resistance in lung cancer. To investigate cellular PAI-1 expression and its correlation with α-SMA expression of CAFs, 34 patients' paraffin-embedded lung adenocarcinoma tissue sections were immunohistochemically stained for PAI-1 and α-SMA. Immunohistochemical analysis of lung adenocarcinoma tissues showed that PAI-1 expression was correlated with that of α-SMA (r = 0.71, p < 0.001). Furthermore, in vitro, α-SMA expression of CAFs was limited by PAI-1 inhibition, and apoptosis of CAFs was increased. In addition, the effectiveness of cisplatin on lung cancer cells co-cultured with CAFs was increased by suppressing α-SMA expression using PAI-1 inhibitor. In lung adenocarcinoma tissues, PAI-1 expression was associated with T factor and TNM stage. Our data suggest that inhibition of PAI-1 increased the chemotherapeutic effect on lung cancer through suppressing the MF characteristics of CAFs. Hence, PAI-1 might be a promising therapeutic target for patients with chemotherapeutic-resistant lung cancer with CAFs.

SUBMITTER: Masuda T

PROVIDER: S-EPMC6433668 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts.

Masuda Takeshi T Nakashima Taku T Namba Masashi M Yamaguchi Kakuhiro K Sakamoto Shinjiro S Horimasu Yasushi Y Miyamoto Shintaro S Iwamoto Hiroshi H Fujitaka Kazunori K Miyata Yoshihiro Y Hamada Hironobu H Okada Morihito M Hattori Noboru N

Journal of cellular and molecular medicine 20190207 4

Plasminogen activator inhibitor-1 (PAI-1) promotes pulmonary fibrosis through increasing myofibroblast (MF) characteristics, expressing alpha-smooth muscle actin (α-SMA) in fibroblasts. Fibroblasts in the tumour stroma are called cancer-associated fibroblasts (CAFs). Some CAFs have MF characteristics and substantially promote tumour progression and chemotherapy resistance. This study determined whether inhibition of PAI-1 suppressed MF characteristics of CAFs and limited chemotherapy resistance ...[more]

PMID: 30734495

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Project description:Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs.

Dataset Information

Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts.

Publications

Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts.

Similar Datasets

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