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

Abstract

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 α (α-SMA) on CAFs in CRC patient tissues. PGRN/α-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 α-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 α-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.

Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis

“…In addition, analysis of the signaling events downstream of TNF showed that TNF-canonical signaling in Tnf ΔARE/+ ;Tnfrsf1b MCKO SFs were comparable with WT control, since JNK and ERK kinases displayed similar phosphorylation kinetics and nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor, α (Nfkbi) showed physiological degradation ( Figure 6H and Supplemental Figure 9, A-C). In contrast, Akt kinase, which belongs to the noncanonical TNF signaling pathway and is associated with positive regulation of cell proliferation and cancer, fails to become phosphorylated, pointing to another level of Tnfr2-mediated cell proliferation regulation downstream of TNF that associates with the PI3K-Akt signaling pathway ( Figure 6I and Supplemental Figure 9D), similar to what has been observed in cancer cells (54,55).…”

Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies

“…Such a cell density/receptor number dependency of the ability of PGRN to interfere with TNF binding is again not straightforwardly compatible with competitive binding inhibition. Third, PGRN enhances TNF-induced TNFR2-mediated proliferation and suppressive activity of regulatory T cells ( 9 ) and PGRN-induced Akt signaling has found to be inhibited by neutralizing TNFR2 antibodies ( 15 , 18 ). Both observations again argue against competitive inhibition of TNF binding by PGRN.…”

TNF Receptor 2 Makes Tumor Necrosis Factor a Friend of Tumors

“…Of note, activating TNFR2 on tumor-promoting cell types, such as fibroblasts might limit tumor cell invasion and metastasis and improve tumor therapy ( 97 – 100 ).…”