Cachexia is a complex syndrome commonly found in cancer patients, characterized by significant weight loss and muscle wasting. Cancer cell-released circulating Hsp70 and Hsp90 play a crucial role in the develop of cachexia in murine models of cancer cachexia. To evaluate whether human cancer induces cachexia through this mechanism, we generated a human pancreatic cancer model in the immunodeficient NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) by orthotopically implanting pancreatic cancer (PC) cells isolated from patient-derived xenograft (PDX). We observed that this model reliably and predictably develops cachexia with good consistency in large numbers of mice such that therapeutic interventions with multiple groups can be compared by adhering to a preset schedule. Using this model, we assessed whether administering neutralizing antibodies against Hsp70 and Hsp90 in mice bearing pancreatic tumor cells originated from human (line G87) alleviates muscle wasting. PC cells isolated from PDX line G87 were orthotopically implanted (3 x 106 cells) into NSG mice (12 weeks of age), with PBS-implanted mice used as a control group. Two weeks later, when the mice began to show early signs of cachexia, they were treated with neutralizing antibodies against Hsp70 and Hsp90 (i.p., 9 µg/mouse/3 days each) or with pre-immune IgG as control. The treatment continued for four weeks. Locomotor activity was monitored over 48 h right before the end of treatment. The IgG-treated tumor-bearing mice displayed significantly higher serum levels of Hsp70/90 in comparison to control mice and exhibited severe muscle wasting. In contrast, treatment with neutralizing antibodies reduced the increase in Hsp70/90 levels in tumor-bearing mice, alleviated body and muscle weight loss, improved grip strength, and increased locomotor activity without affecting tumor volume. Additionally, we found that the antibody treatment blocked p38bMAPK-mediated catabolism through the ubiquitin-proteasome and autophagy-lysosome pathways. Our study demonstrates that neutralizing antibodies against circulating Hsp70/90 significantly alleviates muscle wasting in a mouse model of PDX pancreatic cancer by reducing circulating Hsp70/90 levels to attenuate p38β MAPK-mediated catabolic pathway.
Supported by NIH grant R01 AR063786