More than 90 per cent of human tumors are carcinomas, arising from epithelial cells that are present as continuous sheet of cells lining the cavities and surfaces of the tissues.
Majority of epithelia are organized as polarized monolayers with apical – facing the lumen – and basolateral surfaces – in contact with neighboring cells and basement lamina – composed of different lipids and proteins. Epithelial cells are one of the most polarized cells in body.
This image shows the structure of human Epiregulin. Image credit: Jmol Development Team.
This high fraction of cancer in epithelial tissues could be result of two different reasons: (i) heavy environmental insults in tissues such as skin, gastrointestinal tract, kidney and liver, and (ii) problems with the cellular polarity of the tissue itself. While the role of mutations as a result on constant insults has been well studied in cancer biology, somehow not many people have explored if cellular polarization itself can have something to do with malignancy itself. So far the assumption is that malignancy causes lack of polarization.
Cellular polarization is maintained because of several signaling complexes. Epidermal growth factor receptor (EGFR) is an important regulator of epithelial architecture, polarization and function and it is mainly present (> 90 per cent) in the basolateral surface.
While it was known that in carcinomas, EGFR signaling localization, ligand availability and its negative regulators are altered. But no one had mistrafficked EGFR or altered the cellular polarity by other means to address if alteration to polarity can itself cause cancerous transformation and invasion.
By simply mistrafficking EGFR ligand epiregulin (EREG) from basolateral to apical surface, a team of scientists co-led by Dr Bhuminder Singh, Dr Robert Coffey from Vanderbilt University Medical Center was successful in driving cancerous transformation.
EGFR tyrosine phosphorylation through EREG in apical surface is prolonged compared to basolateral stimulation, likely due to the lack of negative phosphorylation of EGFR and its subsequent ubiquitylation. Cells with apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice (standard models used for immune compromised state) compared with wild type EREG-expressing cells.
In a very well controlled study, reported in the Proceedings of the National Academy of Sciences, Dr Singh and colleagues show that the differences in tumor size cannot be attributed to differences in EREG levels but cellular localization. By removing or replacing key amino acid residues from cytoplasmic domain of EREG, almost all EREG was localized to apical surface, instead of its normal primarily basolateral localization.
Previously how polarity proteins regulate a diverse array of biological processes and how they can contribute to alterations in the behavior of cancer cells has been explored through altering the expression levels but not localization, but the ingenuity of Dr Singh, Dr Coffey’s team was in hitting the hammer on the nail by mistrafficking an EGFR ligand and inducing metastasis. This addresses the question that actually changes in polarized trafficking can cause cancer.
This study does not mean that alteration in cellular polarity is the sole cause of all cancers, but what it means that it is a major contributing factor and hence a possible target for therapeutics.
Does this basic new insight have translational potential? Not immediately, as we do not have approved drugs to revert to polarized state but certainly screens for such drug hold a great potential. Given that invasiveness of cancer cells depends on de-differentiation and lack of polarization if we find agents that can restore polarity they can add valuable arsenal against fight on cancer.
Apart from slowing down cells with large potential of cancerization going down the road of metastasis, this knowledge can be used to device approaches to slow migration of cells. For the elderly where the question is whether the cancer is going to kill them first or old age and hence the dilemma of chemo or radiotherapy, this approach may slow down cancer just enough for one to do away with damaging chemo or radiotherapy entirely.
Pioneering study from the Vanderbilt team has solved an old chicken and egg riddle on polarization and metastasis.
Hopefully this will be followed soon by new direction in cancer research.
Sukant Khurana, Ph.D.
(Author is a neuroscientist, biologist and artist, based at Cold Spring Harbor Laboratory, NY, USA. Website: www.brainnart.com. Twitter: @brainnart).
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Bibliographic information: Singh, B., Bogatcheva, G., Washington, M. K., & Coffey, R. J. 2013. Transformation of polarized epithelial cells by apical mistrafficking of epiregulin. PNAS, 110 (22), 8960 – 8965; doi: 10.1073/pnas.1305508110
