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Fibroblast activation in cancer: when seed fertilizes soil

Abstract

In solid cancers, activated fibroblasts acquire the capacity to provide fertile soil for tumor progression. Specifically, cancer-associated fibroblasts (CAFs) establish a strong relationship with cancer cells. This provides advantages to both cell types: whereas cancer cells initiate and sustain CAF activation, CAFs support cancer cell growth, motility and invasion. This results in tumor progression, metastasis and chemoresistance. Numerous studies have detailed the mechanisms involved in fibroblast activation and cancer progression, some of which are reviewed in this article. Cancer cells and CAFs are “partners in crime”, and their interaction is supported by inflammation. An understanding of the enemy, the cancer cell population and its “allies” should provide novel opportunities for targeted-drug development.

Molecular mechanism of fibroblast activation. a Normal fibroblasts are the most common cell type in the extracellular matrix and are responsible for the synthesis of collagens and fibrilar proteins. Under normal conditions, fibroblasts maintain tissue homeostasis and contribute to proper cell communication and function. Fibroblasts can be activated by a diverse set of factors secreted from cancer or immune cells. Not only growth factors such as TGF-β, PDGF, HGF and FGF but also interleukins, metalloproteinases and reactive oxygen species can promote activation. Likewise, transcriptional factors such as NF-κB and HSF-1 play an important role, as do the gene family of metalloproteinase inhibitors, Timp and the NF-κB subunit, p62. Interestingly, fibroblasts themselves can stimulate cancer cells to support activation further. b Once activated, fibroblasts undergo a phenotype switch and become cancer-associated fibroblasts (CAFs) expressing various markers such as α-SMA, FSP1, vimentin and periostatin. c Recently, the LIF/GP130/IL6-R pathway has been identified as a signaling cascade involved in fibroblast activation. Upon LIF stimulation, JAK is phosphorylated and further activates STAT3, a transcriptional factor that is then translocated into the nucleus where it promotes the transcription of genes responsible for cell growth, differentiation, proliferation and apoptosis. Ruxolitinib can inhibit JAK and prevent STAT3 activation. Further on, the maintenance of JAK activation is supported by epigenetical changes and post-translational modifications. Once pSTAT3 is acetylated by histon acetyltransferase, p300, it leads to the loss of expression of SHP-1, which is a negative regulator of the JAK/STAT pathway. Silencing of SHP-1 steers the constitutive activation of JAK and STAT3

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Acknowledgments

We thank Dr. G. Meneguzzi and Dr. S.E. Acton for critical reading of the manuscript.

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Correspondence to Cedric Gaggioli.

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This work was supported by the French Government (National Research Agency, ANR) through the “Investments for the Future” of Labex Signalife (program reference no. ANR-11-LABX-0028-01) and by grants from ARC “PJA20151203452”, ANR “ANR-14-RARE-0004-02” and the Debra UK foundation. S.E.K. is the recipient of a Labex Signalife fellowship.

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Kuzet, SE., Gaggioli, C. Fibroblast activation in cancer: when seed fertilizes soil. Cell Tissue Res 365, 607–619 (2016). https://doi.org/10.1007/s00441-016-2467-x

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Keywords

  • Carcinoma-associated fibroblasts
  • Tumor microenvironment
  • Inflammation
  • Cancer