EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis

Abstract

Exploring the parallels between wound healing and epithelial cancers, Sundaram et al. elucidate the mechanism by which cancer cells hijack the wound healing switch to enhance invasion and metastasis in head and neck squamous cell carcinoma.

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

“…Second, high levels of p-ERK1/2, a measure of MAPK signaling, were reported in TA cells (21). Third, RSPO3, a Wnt sensitizer, was shown to inhibit MAPK signaling and block osteogenic differentiation of adipocyte stem cells in culture (22,23). Therefore, the intestinal samples of C59-or vehicle-treated mice were stained for p-ERK1/2 by immunohistochemistry (IHC).…”

A wound-healing program is hijacked to promote cancer metastasis

“…This paper further elaborates on the downstream mechanisms involved, showing that FSTL1 promotes expression of the matrix metalloprotein MMP9, which can degrade extracellular matrix, through an effect on Wnt and mitogen-activated protein kinase (MAP kinase) signaling. Additionally, Sundaram et al (2017) find that the miR-198 target DIA PH, which is known to promote migration, is increased in this setting. The physiological relevance of these findings is supported by in vivo data the authors provide showing that knockdown of FSTL1 and DIA PH collaboratively block pulmonary metastases in a tail vein injection model and by clinical data showing that HNS CC patients whose tumors express high levels of both factors have a very poor prognosis (Sundaram et al, 2017).…”

“…Although typically diagnosed as a local condition, most patients ultimately succumb as a result of metastasis, and therefore a detailed understanding of the mechanisms involved may yield important therapeutic opportunities. EGFR has long been considered an important oncogenic driver in HNS CC, and the work by Sundaram et al (2017) demonstrates yet another mechanism by which activation of this receptor contributes to pathogenesis in this disease. Unfortunately, therapeutic targeting of the EGFR pathway has been a relative disappointment to date, despite numerous clinical trials involving both antibodies and small molecules that inhibit EGFR itself (Sharafinski et al, 2010).…”

Cancer: the dark side of wound healing

“…Many of these events also operate during cancer progression . A number of promigratory proteins required for keratinocyte migration are also abundantly expressed in epithelial cancers . Here we provide a discourse into the commonalities between wound healing and epithelial cancers, with a focus on invasive and metastatic squamous cell carcinomas (SCCs).…”

“…This creates a feed‐forward loop which locks the switch in its defective position , creating a cellular state resembling a prolonged wound healing phase. In this state, uncontrolled cell migration is highly conducive to metastasis . The effects of this faulty switch may not be limited to epithelial cancers.…”