Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells

Abstract

The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here we show that cancer cells resistant to Hsp70 inhibitors in vitro remain sensitive to them in vivo, revealing the pathogenic significance of Hsp70 in tumor stromal cells rather than tumor cells as widely presumed. Using transgenic mouse models of cancer, we found that expression of Hsp70 in host stromal cells was essential to support tumor growth. Furthermore, genetic ablation or pharmacological inhibition of Hsp70 suppressed tumor infiltration by macrophages needed to enable tumor growth. Overall, our results illustrate how Hsp70 inhibitors mediate the anti-cancer effects by targeting both tumor cells and tumor stromal cells, with implications for the broad use of these inhibitors as tools to ablate tumor-associated macrophages that enable malignant progression.

Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations

“…From a hit-to-lead campaign, a second generation molecule JG-98 was identified with greater affinity for Hsp70, and stronger anti-cancer effects in animal models 24 . An unusual benefit of these inhibitors is that they not only reduce viability of cancer cells, but also reduce infiltration of tumor-associate macrophages 25 . Accordingly, by acting through the tumor stroma, JG-98 shows potent anti-cancer effects even if tumor is formed by cancer cells resistant to it 25 .…”

“…An unusual benefit of these inhibitors is that they not only reduce viability of cancer cells, but also reduce infiltration of tumor-associate macrophages 25 . Accordingly, by acting through the tumor stroma, JG-98 shows potent anti-cancer effects even if tumor is formed by cancer cells resistant to it 25 . Though these inhibitors do not distinguish between highly homologous Hsp70 family members, focusing on cancer specific functions addresses the daunting challenge of safety of Hsp70 inhibitors.…”

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

“…These factors act in concert to maintain a pro-metastatic immune-suppressed tumor microenvironment that favors tumorigenesis [132]. Other tumor-infiltrating cells, such as tumor-associated macrophages (TAMs), may also be dependent on HSF1 activity to maintain high levels of HSPs, whereby Hsp72 was shown to be important for TAM infiltration of tumors [133]. TAMs are known to secrete growth factors favoring tumor growth.…”

“Heat shock protein 70 in pancreatic diseases: Friend or foe”

“…Early evidence towards this fact was shown by Gabai et al, where HSP70 inhibitors that were not effective in vitro on resistant cancer cells were surprisingly able to reduce tumor growth in vivo, a finding, they attribute to the inhibition of HSP70 in the stroma. 65 Together, Minnelide appears to combine stromal modulation with cancer cell death that may hold the key to designing stroma directed therapy in the future.…”