Is transforming growth factor beta signalling required for breast cancer metastatic cell motility?

Background

In many cell types, transforming growth factor beta (TGFβ) results in a growth inhibitory signal, which is mediated by transducers of the Smad family. In tumour cells, however, TGFβ-dependent antiproliferative control is lost and cells acquire the ability to replicate in TGFβ-rich environments. Furthermore, molecular and clinical evidence points to a role for TGFβ signalling in cancer progression and metastasis; however, it is unclear at which points of the metastatic process TGFβ signalling occurs and whether it is necessary and/or sufficient to elicit cancer cell motility.

Methods

To address these questions, MTln3E rat breast cancer cells were used as a relevant model system. When injected into the mammary fat pad of nude mice, these cells form a primary tumour from which motile cells will depart to form metastasis in the lymph nodes and the lungs. To gain insight into TGFβ signalling in vivo, MTln3E cells were engineered to express GFPSmad2. This allowed monitoring Smad-dependent TGFβ signalling in vivo by imaging the primary tumour and in lymph-node metastasis using multiphoton confocal microscopy.

Results

The results indicate that TGFβ signalling, measured by cytoplasmic to nuclear translocation of GFPSmad2, does not occur ubiquitously within the primary tumour. On the contrary, TGFβ signalling appears most prominent in movement-rich areas. Within these areas, all the cells that have acquired a motile phenotype display active TGFβ signalling. Furthermore, none of the motile cells display nuclear exclusion of GFPSmad2.

Conclusion

Together these data suggest that TGFβ signalling may be required in metastatic cells, possibly to enable acquisition of the motility phenotype. However, as nuclear localisation of GFPSmad2 is observed also in nonmotile cells, TGFβ signalling alone may not be sufficient to elicit cell motility in primary tumour cells.