Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor...

Area of Science:

• Oncology
• Cell Biology
• Immunology

Background:

• The tumor microenvironment (TME) is crucial for tumor growth, with inflammation and reactive stroma being key features in prostate cancer.
• Cancer-associated fibroblasts (CAFs) contribute to the inflammatory TME by secreting cytokines, but the initiating factors for reactive stroma formation are not fully understood.

Purpose of the Study:

• To investigate if tumor-secreted extracellular Hsp90 alpha (eHsp90α) initiates the formation of a reactive stroma in prostate cancer.
• To elucidate the signaling pathways and downstream effects of eHsp90α in prostate stromal fibroblasts (PrSFs).

Main Methods:

• PrSFs were treated with exogenous Hsp90α or conditioned medium from eHsp90α-expressing prostate cancer cells.
• Evaluated signaling, motility, and expression of reactive markers in PrSFs.
• Utilized ELISA assays to characterize Hsp90α-mediated secreted factors.

Main Results:

• eHsp90α exposure upregulated IL-6 and IL-8 secretion in PrSFs via MEK/ERK and NF-κB pathways.
• eHsp90α promoted rapid and sustained activation of signal transducer and activator of transcription (STAT3).
• eHsp90α induced the expression of MMP-3, a mediator of fibrosis and myofibroblast phenotype.

Conclusions:

• Extracellular Hsp90 alpha (eHsp90α) acts as a signaling transducer that leads to an inflammatory and reactive stroma.
• This eHsp90α-mediated stromal response confers properties that enhance prostate cancer progression.