Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Heat shock protein 70 (Hsp70) is a stress-induced chaperone protein implicated in cancer initiation and progression.
• Hsp70 is considered a promising therapeutic target for cancer treatment.
• Previous understanding presumed Hsp70's primary role was within tumor cells.

Purpose of the Study:

• To investigate the role of Hsp70 in cancer progression, particularly in resistant cell lines.
• To determine the specific cellular compartment (tumor vs. stromal) where Hsp70 exerts its pathogenic influence.
• To elucidate the mechanism by which Hsp70 inhibitors exert their therapeutic effects in vivo.

Main Methods:

• Utilized in vitro and in vivo models of cancer.
• Employed transgenic mouse models to study Hsp70 expression in host stromal cells.
• Investigated the effects of genetic ablation and pharmacologic inhibition of Hsp70.
• Assessed tumor infiltration by macrophages.

Main Results:

• Cancer cells resistant to Hsp70 inhibitors in vitro remained sensitive in vivo.
• Hsp70 expression in host stromal cells was critical for tumor growth.
• Inhibition of Hsp70 reduced tumor infiltration by growth-promoting macrophages.
• Hsp70 inhibitors demonstrated anticancer effects by targeting both tumor and stromal cells.

Conclusions:

• Hsp70's pathogenic role in cancer is significantly mediated through tumor stromal cells.
• Hsp70 inhibitors are effective in vivo, even against tumors with in vitro resistance.
• Hsp70 inhibition suppresses tumor growth by reducing pro-tumorigenic macrophage infiltration.
• Hsp70 inhibitors have potential as therapeutic agents targeting tumor-associated macrophages for cancer treatment.