Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Autor: Sijing Li, Ligong Lu, Hongzhi Du, Li Sun, Meixiao Zhan, Lifei Han, Xin Shi, Yang Liu, Wei Yu, Jinyong He, Xiaohui Wei, Hao-Lin Hu, Shengtao Yuan, Chenfei Wang, Hongyang Li
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Adult
Stromal cell
Microenvironment
PAI-1
Adipose tissue
lcsh:Medicine
Mice
Nude
Breast Neoplasms
Biochemistry
Metastasis
Extracellular matrix
03 medical and health sciences
Mice
Phosphatidylinositol 3-Kinases
Breast cancer
Cell Line
Tumor
Collagen network
Breast Cancer
Plasminogen Activator Inhibitor 1
medicine
Adipocytes
Animals
Humans
lcsh:QH573-671
Neoplasm Metastasis
skin and connective tissue diseases
Molecular Biology
0303 health sciences
PLOD2
Mice
Inbred BALB C
business.industry
lcsh:Cytology
Procollagen-Lysine
2-Oxoglutarate 5-Dioxygenase
Research
030302 biochemistry & molecular biology
lcsh:R
Forkhead Transcription Factors
Cell Biology
3T3 Cells
Middle Aged
medicine.disease
Metastatic breast cancer
Cancer cell
Cancer research
Female
Collagen
business
Proto-Oncogene Proteins c-akt
Zdroj: Cell Communication and Signaling : CCS
Cell Communication and Signaling, Vol 17, Iss 1, Pp 1-18 (2019)
ISSN: 1478-811X
Popis: Background Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear. Methods Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes. Results It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer. Conclusion In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment. Electronic supplementary material The online version of this article (10.1186/s12964-019-0373-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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