# Identification of key tumor cell-released factors that induce cachexia

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $525,564

## Abstract

Project summary
Cancer cachexia, characterized by muscle wasting, is seen in ~60% of cancer patients and a major contributor
to the morbidity and mortality associated with cancer. Consequently, cachexia is the direct cause of ~1/3 of
cancer-related deaths. We must manage cachexia because preserving muscle and body mass could promote
response to cancer treatment, improve patient physical condition to withstand cancer treatment, and prolong
survival. However, there is no standardized assessment or established treatment for cancer cachexia due to
the poor understanding of its etiology. A major difficulty in understanding cachexia is the high complexity of
cancer milieu, in which many contributing factors have been proposed, but the key mediators of cachexia remain
elusive. Supported by R01 AR063786, we discovered recently that diverse types of cachexia-inducing tumors
release high levels of extracellular Hsp70 & Hsp90 that are associated with extracellular vesicles (EVs), which
is necessary and sufficient for the development of muscle wasting in mice due to their activation of Toll-like
receptor 4 (TLR4) on muscle cells that activates protein degradation pathways. In addition, elevation of serum
Hsp70 & Hsp90 in tumor-bearing mice is required for the elevation of inflammatory cytokines (TNFα and IL-6)
that promote muscle wasting. These data indicate that elevated circulating Hsp70 & Hsp90 are the key driving
force of cancer-induced muscle wasting and systemic inflammation, thus, could be biomarkers and therapeutic
targets of cancer cachexia. These findings provide an opportunity for etiology-based diagnosis and intervention
of cancer cachexia. However, animal models do not always recapitulate complex events that occur in cancer
cachexia in humans, it will be important moving forward to validate the importance of circulating Hsp70 & Hsp90
in human cancer cachexia. Although multiple clinical studies found that serum Hsp70 & Hsp90 levels in cancer
patients increase with the development of pathological grade and clinical stage, and the increase correlates with
mortality, whether elevated serum Hsp70 & Hsp90 correlate with and cause human cancer cachexia are
unknown. Therefore, we propose to test the hypothesis that tumor-released extracellular Hsp70 & Hsp90 are
biomarkers and therapeutic targets of human cancer cachexia. We will conduct a longitudinal patient study to
determine whether elevated serum Hsp70 & Hsp90 are biomarkers of human cancer cachexia that correlate with
natural history of advanced malignancies and clinical outcome. In addition, we will determine whether human
cancer cell release of extracellular vesicle-associated Hsp70 & Hsp90 are causal to muscle wasting and
shortened survival by studying patient-derived primary cancer cells in vitro, and mice bearing patient-derived
xenografts (PDX) of cancer in vivo. Finally, we will conduct experimental therapy of cachexia in PDX-bearing
mice by blocking Hsp70 & Hsp90 release using a pharmacolog...

## Key facts

- **NIH application ID:** 10144389
- **Project number:** 5R01AR063786-07
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Syed H Jafri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $525,564
- **Award type:** 5
- **Project period:** 2013-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144389

## Citation

> US National Institutes of Health, RePORTER application 10144389, Identification of key tumor cell-released factors that induce cachexia (5R01AR063786-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10144389. Licensed CC0.

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