Abstract
Later stages of secondary lymphedema are associated with the massive deposition of adipose tissue (AT). The factors driving lymphedema-associated AT (LAT) expansion in humans remain rather elusive. We hypothesized that LAT expansion could be based on alterations of metabolic, adipogenic, immune and/or angiogenic qualities of AT. AT samples were acquired from upper limbs of 11 women with unilateral breast cancer-related lymphedema and 11 healthy women without lymphedema. Additional control group of 11 female breast cancer survivors without lymphedema was used to assess systemic effects of lymphedema. AT was analysed for adipocyte size, lipolysis, angiogenesis, secretion of cytokines, immune and stem cell content and mRNA gene expression. Further, adipose precursors were isolated and tested for their proliferative and adipogenic capacity. The effect of undrained LAT- derived fluid on adipogenesis was also examined. Lymphedema did not have apparent systemic effect on metabolism and cytokine levels, but it was linked with higher lymphocyte numbers and altered levels of several miRNAs in blood. LAT showed higher basal lipolysis, (lymph)angiogenic capacity and secretion of inflammatory cytokines when compared to healthy AT. LAT contained more activated CD4+ T lymphocytes than healthy AT. mRNA levels of (lymph)angiogenic markers were deregulated in LAT and correlated with markers of lipolysis. In vitro, adipose cells derived from LAT did not differ in their proliferative, adipogenic, lipogenic and lipolytic potential from cells derived from healthy AT. Nevertheless, exposition of preadipocytes to LAT-derived fluid improved their adipogenic conversion when compared with the effect of serum. This study presents results of first complex analysis of LAT from upper limb of breast cancer survivors. Identified LAT alterations indicate a possible link between (lymph)angiogenesis and lipolysis. In addition, our in vitro results imply that AT expansion in lymphedema could be driven partially by exposition of adipose precursors to undrained LAT-derived fluid.
Highlights
Later stages of secondary lymphedema are associated with the massive deposition of adipose tissue (AT)
The main aim of this study was to evaluate whether AT qualities possibly contributing to lymphedema-associated AT (LAT) accumulation are affected by breast cancer related secondary lymphedema in human
Women from LYM group developed lymphedema 0–13 years after primary anti-tumour treatment and lymphedema lasted for 2–9 years until they were indicated for liposuction
Summary
Later stages of secondary lymphedema are associated with the massive deposition of adipose tissue (AT). HS Human serum ISO Isoproterenol LAT Lymphedema-associated adipose tissue LDL Low-density lipoprotein LYM group Women with unilateral lymphedema stage II in upper extremity MSC Mesenchymal stem cells NOLYM group Women-breast cancer survivors-without unilateral lymphedema ORO Oil Red O staining PCA Principal component analysis SVF Stromal-vascular fraction. The factors driving this lymphedema-associated AT (LAT) expansion in humans remain still rather elusive, the causal link between defects in lymphatic system and aberrant AT accumulation was demonstrated in several animal models. Several lines of evidence suggest that the leaking lymph or undrained interstitial fluid modify microenvironment and various qualities of AT eventually promoting AT expansion This concept has been studied mostly in experimental animals and the validity of this concept in humans still needs to be tested. Angiogenic, immune and metabolic properties of healthy and lymphedema-associated AT and adipose precursors derived from these tissues
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