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.

Linlin Wang,Yihang Shen,Xia Ren,Guosheng Jiang,Xia Li,Dong Yang,Jing Tian,Taotao Dong,Aiqin Gao

doi:10.18632/oncotarget.15461

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.

Highlights

As one of the most common malignant tumors in the world, the mortality of colorectal cancer (CRC)has declined in recent years, greatly attributing to early screening program and ameliorated therapy regimens, such as neoadjuvant chemotherapy, molecular target therapy, biotherapy, and so on
To detect the correlation of PGRN expression in CRC cells and α-SMA in fibroblasts, IHC staining for PGRN and α-SMA was performed in 77 CRC patient tissues
Survival analysis showed that overall survival (OS) and disease free survival (DFS) of CRC patients with both high expression of PGRN and α-SMA were much worse than patients with both low expression of PGRN and α-SMA (p = 0.029 and 0.004, respectively; Figure 1B and 1C; Supplementary Tables 1 and 2)

Summary

Introduction

As one of the most common malignant tumors in the world, the mortality of colorectal cancer (CRC)has declined in recent years, greatly attributing to early screening program and ameliorated therapy regimens, such as neoadjuvant chemotherapy, molecular target therapy, biotherapy, and so on. As one of the most common malignant tumors in the world, the mortality of colorectal cancer (CRC). A detailed understanding of molecular mechanisms regulating the development, progression, and metastasis of a malignant colorectal tumor may lead to improvements in patient therapy outcome. It has been reported that a reactive microenvironment played important roles in tumor occurrence and progression [4, 5]. Cancer associated fibroblasts (CAFs) are one kind of the main cellular components in tumor microenvironment, and play important role in proliferation, migration and invasion of tumor cells through inducing epithelial mesenchymal transformation (EMT), secreting matrix metalloproteinase (MMP) or growth factors [4, 6,7,8,9,10]. The mechanism of transformation from resident fibroblasts to CAFs is still elusive

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Conclusion