Macrophages protect against loss of adipose tissue during cancer cachexia

Abstract

BackgroundCancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti‐inflammatory drugs failed to show distinct cachexia‐inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)‐associated cachexia.MethodsA transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell‐mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro‐inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care.ResultsWe identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography‐based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell‐mediated inflammation defect resulted in reduced expression of pro‐inflammatory cytokines in the serum of HCC‐bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia‐associated fat loss. Defective myeloid cell‐mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer‐induced fat loss.ConclusionsMyeloid cell‐mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer‐induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti‐inflammatory drugs.

Cachexia, a Systemic Disease beyond Muscle Atrophy

“…Functional studies in cancer patients have found a positive relationship between immune cell infiltration (granulocyte/phagocytes, and CD3−CD4+ cells) and muscle mass status, whereas a negative correlation has been established between CD8 T cells and muscle catabolic pathways [40]. In a murine HCC (Hepatocellular Carcinoma) model, a decreased macrophage infiltration in visceral tissue has been associated with the loss of adipose tissue [39,41], whereas in clinical studies, activated macrophages have been found to be infiltrated in fat. To date, the mechanisms by which macrophages modulate adipocyte function are still unclear [42][43][44][45].…”

The immunological regulation of cancer cachexia and its therapeutic implications

“…The pro-cachectic acute phase response is not seen, however, in 66C4 subclone of 4TI mice in which MDSC expansion does not occur [53] . Defects in myeloid cell-mediated inflammation has also been shown to result in reduced expression of pro-inflammatory cytokines in the serum of mice with hepatocellular carcinoma [54] . Interestingly, this led to enhanced loss of adipose tissue and decreased macrophage number in visceral adipose tissue, suggesting a possible local role for macrophages in the regulation of cancer-induced fat loss [54] .…”

“…Defects in myeloid cell-mediated inflammation has also been shown to result in reduced expression of pro-inflammatory cytokines in the serum of mice with hepatocellular carcinoma [54] . Interestingly, this led to enhanced loss of adipose tissue and decreased macrophage number in visceral adipose tissue, suggesting a possible local role for macrophages in the regulation of cancer-induced fat loss [54] . These findings imply that myeloid cell-mediated inflammation confers a beneficial function in these rodents, and may provide a potential explanation for the failure of several antiinflammatory drugs in treating cachexia.…”

Biomarkers for cancer cachexia: where do we stand?

“…Potential biomarker should not only be predictive but should also allow to monitor the progression of cachexia and the effects of putative therapies. However, while there are a number of biomarker candidates (for comprehensive overview, see Loumaye and Thissen 2 ) such as TGF‐β, 3 activin A, 4 myostatin, 5,6 systemic inflammation, 7 pro‐inflammatory cytokines and chemokines, 8–10 micro RNAs, 11–18 and protein degradation products, 19–21 none have been clinically established, except for the hallmark symptom weight loss in combination with additional factors such as muscle mass and strength 22 . In addition, markers of fat loss such as leptin, 23,24 free fatty acids, 25,26 glycerol, 27 and zinc‐α2‐glycoprotein 28 may be of clinical interest.…”