Abstract
Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.
Highlights
Involuntary body weight loss, or cachexia, is a devastating consequence of many advanced-stage cancers, and cachexia affects up to 80% of all cancer patients [1]
Induced a 35% and 33% decrease in myotube diameter, respectively. These findings demonstrate that factors released from human pancreatic cancer and stromal cells induce significant myotube atrophy and that the atrophy induced by cancer/stromal cell interactions is greater than that induced by either cell type alone
Were significantly increased at 15 minutes, 30 minutes, and 3 h of IL-8 treatment (Figure 5H,J), whereas levels of phospho/total p38 were significantly decreased following 15 minutes, 30 minand 1 hour of IL-8 treatment (Figure 5I,J). These findings suggest that the exposure of skeletal muscle cells to IL-8 activates several pathways implicated in cancer cachexia
Summary
Involuntary body weight loss, or cachexia, is a devastating consequence of many advanced-stage cancers, and cachexia affects up to 80% of all cancer patients [1]. Cachexia has a profound impact on the quality of life as it associates with weakness, functional decline, and loss of independence [3]. Cachexia represents a major barrier to treatment, such as surgery or chemotherapy, as outcomes are highly dependent on functional reserve [4]. This contributes to a significantly decreased survival time in cachectic cancer patients [5]. Identifying modifiable factors essential to the development of cancer cachexia is imperative
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