Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer

Cancer associated fibroblasts (CAFs) are a crucial cellular component in tumor microenvironment and could promote tumor progression. CAFs are usually derived from resident fibroblasts, which undergoing an activated process stimulated by tumor cells. However, the agents and mechanism driving this switch have not yet been elucidated. Progranulin (PGRN), a well acknowledged secreted glycoprotein, could promote proliferation and angiogenesis of colorectal cancer (CRC) cells, and high expression of PGRN correlated with patient poor prognosis. Whether PGRN has effects on the function of stromal fibroblasts is unknown. Herein we found that there was a positive correlation between PGRN expression of CRC cells and expressions of smooth muscle actin a (alpha-SMA) on CAFs in CRC patient tissues. PGRN/alpha-SMA co-expression was positively correlated with CRC patient poor prognosis. Co-cultured with CRC cells or human recombinant PGRN (rPGRN), the expression of Ki67, fibroblast activation protein (FAP) and alpha-SMA in fibroblasts were all up-regulated significantly, accompanying with elevated cellular proliferation, migration and contraction. Whilst co-cultured with PGRN-silenced CRC cells, these functions were down-regulated. Studies of the underlying molecular mechanism demonstrated that either tumor necrosis factor receptor 2 (TNFR2)/Akt or the extracellular regulated kinase (ERK) signaling pathway contributed to modulate of Ki67, FAP, and alpha-SMA expression, and correlated to abilities of proliferation, migration and contraction in fibroblasts. In conclusion, PGRN plays an important role in activation of CRC fibroblasts, which may be taken as a prospective target of CRC therapy.