Targeting extracellular Hsp90: A unique frontier against cancer

Abstract

The molecular chaperone Heat Shock Protein-90 (Hsp90) is known to interact with over 300 client proteins as well as regulatory factors (eg. nucleotide and proteins) that facilitate execution of its role as a chaperone and, ultimately, client protein activation. Hsp90 associates transiently with these molecular modulators during an eventful chaperone cycle, resulting in acquisition of flexible structural conformations, perfectly customized to the needs of each one of its client proteins. Due to the plethora and diverse nature of proteins it supports, the Hsp90 chaperone machinery is critical for normal cellular function particularly in response to stress. In diseases such as cancer, the Hsp90 chaperone machinery is hijacked for processes which encompass many of the hallmarks of cancer, including cell growth, survival, immune response evasion, migration, invasion, and angiogenesis. Elevated levels of extracellular Hsp90 (eHsp90) enhance tumorigenesis and the potential for metastasis. eHsp90 has been considered one of the new targets in the development of anti-cancer drugs as there are various stages of cancer progression where eHsp90 function could be targeted. Our limited understanding of the regulation of the eHsp90 chaperone machinery is a major drawback for designing successful Hsp90-targeted therapies, and more research is still warranted.

Nonpreferential but Detrimental Accumulation of Macrophages With Clonal Hematopoiesis-Driver Mutations in Cardiovascular Tissues—Brief Report

“…Some of these upregulated genes can function intracellularly to activate macrophages or be released to the extracellular space to amplify inflammatory activities through other cells. 29 – 31 We observed that these mutations casted similar impacts on both the CCR2+ and CCR2− macrophages, suggesting a pan-immune activation associated with the mutations.…”

Non-preferential, but detrimental accumulation of macrophages with clonal hematopoiesis-driver mutations in cardiovascular tissues

“…Similar immune activation phenotypes were shown in the heart macrophages with additional chemokines (Figure 2A-D) upregulated in the carriers. Many of these upregulated genes can function intracellularly to activate macrophages or be released to the extracellular space to amplify inflammatory activities through other cells 26–28 . On the other hand, our data also showed distinctive impacts of CHIP on plaque and cardiac macrophage functions and metabolism.…”

Distinct patterns of proteostasis network gene expression are associated with different prognoses in melanoma patients

“…To understand whether different clinical attributes could underlie differences in survival across CM patients, we assessed several melanoma characteristics that are dependent on the PN: pigmentation, rate of subsequent metastasis, drug response and tumour thickness across our patient sub-groups 21,22 wherever data was available. We found that in primary cohorts, samples in group A had higher pigmentation scores and lower subsequent metastasis than those in group B, as well as a trend towards reduced tumour thickness (Supplementary Fig.…”