Furthermore, possibly due to SV-L1CAM being seemingly tumour-associated, nobody had so far challenged the FTY720 hypothesis that SV-L1CAM is also functionally the most important L1CAM variant for tumour progression. The surprising finding of the Carfilzomib inquirer present study is that FL-L1CAM rather than SV-L1CAM is the important determinant of metastasis. This revises the so far prevalent notion that this full length isoform should not play a role in carcinogenesis and tumour progression, as �C due to its assumed restriction to neuronal tissues �C it was thought to be mainly associated with normal physiology or specific neuronal disorders. Importantly, our present finding shows that the FLL1CAM variant and not the SV-L1CAM splice variant was inducible by exposure of tumour cells to pro-metastatic factors. It has already been reported that the expression of L1CAM can be induced by TGF-b1 in general. Interestingly, in the present study we detected a selective up-regulation of FL-L1CAM upon exposure of SKOV3ip-lacZ human ovarian carcinoma cells to TGF-b1and of HCT-116 human colon carcinoma cells to HGF, which are known pro-metastatic factors. Our study shows that quantity is not the major determinant, as FL-L1CAM, although expressed at lower levels than SV-L1CAM, is still the crucial factor in the specific process of metastatic colonization. Thus, these data allow us to assign a metastasis-promoting function for the previously unsuspected FL-L1CAM rather than for the usual suspect SV-L1CAM. They further support the idea of alternative splicing as a tightly regulated process and suggest that marginal imbalances in the splicing homeostasis, as provoked by pro-metastatic stimuli, are sufficient to elicit or to exacerbate tumours. In order to confirm that FL-L1CAM accounted for the metastasis-promoting function of this adhesion molecule in vivo, we inoculated HT1080lacZ-K15 that selectively overexpressed either FL-L1CAM or SV-L1CAM. This cell line allows separate functional studies for each isoform without interference through the expression of the other variant, since it does not express any L1CAM variant endogenously. Indeed, elevated levels of FLL1CAM but not of SV-L1CAM promoted experimental lung metastasis in mice. We ruled out that this metastasis-promoting effect simply relied on increased tumour cell proliferation, a finding which is in accordance with previous results.