The interaction between
tumors and their microenvironments leads to a vicious cycle, which strengthens both immune suppression and
cancer progression. The present study demonstrates for the first time that
tumor-associated dendritic cells (TADCs) are a source of
resistin, which is responsible for increasing
lung cancer epithelial-to-mesenchymal transition. In addition, large amounts of
resistin in the condition medium (CM) of TADCs increase cell migration and invasion, as well as the osteolytic bone metastatic properties of
lung cancer cells. Neutralization of
resistin from TADC-CM prevents the advanced
malignancy-inducing features of TADC-CM. Significantly elevated levels of
resistin have been observed in mice transplanted with
lung cancer cells,
tumor-infiltrating CD11c(+) DCs in human
lung cancer samples and
lung cancer patients' sera. Induction of
lung cancer progression by TADC-derived
resistin is associated with increased expression of
Wolf-Hirschhorn syndrome candidate 1 (WHSC1), a
histone methyltransferase.
Resistin-induced WHSC1 increases the dimethylation of
histone 3 at
lysine 36 and decreases the trimethylation of
histone 3 at
lysine 27 on the promoter of Twist, resulting in an enhancement of the expression of Twist. Knockdown of WHSC1 by
small interfering RNA transfection significantly decreases
resistin-mediated
cancer progression by decreasing the upregulation of Twist, suggesting that WHSC1 plays a critical role in the regulation of Twist by epigenetic modification. Furthermore, mice that received antiresistin
antibodies showed a decreased incidence of
cancer development and
metastasis. These findings suggest that TADC-derived
resistin may be a novel candidate in promoting the development of
lung cancer.