238 Chapter 8 under these conditions, an increase in nuclear ERK1/2 is observed (39), as well as persistent phosphorylated nuclear Jun (37). The latter being a well-known transcription factor which induces oncogenic transformation (40). Besides ERK1/2 signaling, endosome-carried MET can also regulate activation of oncogenic STAT3 and Rac1, positioning endocytic trafficking as a regulator of cell survival, invasion, and metastasis (41, 42). Possibly, the molecular mechanisms regulating endocytic trafficking and endosomal signaling may provide new leads for cancer therapeutics (41). Mitochondrial trafficking of MET has been described (43). Furthermore, it is known that a disturbance in mitochondrial fission and fusion (43) is associated with abnormal cell function (44, 45) and human disease, such as carcinogenesis (46). More specifically, it has been shown that an increase in mitochondrial fission, and upregulation of fission components Fis1 (47) and Drp1 (48) results in tumorigenesis and metastasis (49, 50). It has also been shown that upon fission fragmented mitochondria reposition to the leading edge of cancer cells, from where they facilitate the formation of lamellipodia or invadopodia (51), which are imperative for cell migration and invasion (52). Recently, Yu et al. (53) illustrated that MET can be trafficked towards the mitochondria, where it phosphorylates Fis1 at Tyr38 (Fis1 pY38). Subsequently, Fis1 pY38 promotes Drp1 assembly at mitochondria triggering fission. The fragmented mitochondria facilitated actin filament remodeling, as well as lamellipodia, or invadopodia formation, ultimately fueling metastasis of hepatocellular carcinoma cells. Taking the previous two paragraphs into consideration, it is clear that oncogenic MET signaling is not restricted to the cell membrane, but can also occur post-internalization from endosomes and mitochondria. Consequently, it can be stated that membranous MET immunoreactivity is not sufficient to stratify patient eligible for treatment with MET targeted therapies and that it is necessary to develop an updated scoring system that also accounts for cytoplasmic MET immunoreactivity. In chapter 3, the association between absent membranous MET immunoreactivity and poor prognosis, of patients diagnosed with OSCC and HPV negative oropharyngeal SCC, was explained by a tight balance between MET expression and – epithelial – tissue homeostasis. However, the assumption that cytoplasmic MET staining could represent endosomal and/or mitochondrial signaling of MET, provides an alternative explanation for this observation. Yet, whether tumors showing solely cytoplasmic immunoreactivity for MET show high levels of MET signaling needs further investigation.
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