Targeting mesenchymal exaptation to mitigate tumor growth

Abstract

In order to metastasize, epithelial cells either acquire an amoeboid or mesenchymal morphology. The end result of these architectural changes is that the once rigid epithelial cell loses intercellular junctions and detaches from the surrounding substratum; it becomes more flexible and motile. Morphological adaptations involved in epithelial-to-mesenchymal transition (EMT) are a result of a number of molecular changes, including down modulation of E-cadherin (Ecad) and expression of the mesenchymal marker vimentin. Basu and colleagues demonstrate that advanced-stage HNSCC are comprised of heterogeneous masses with Ecad-expressing epithelial cells interspersed with mesenchymal-like tumor cells expressing vimentin. Increased Ecad levels are frequently correlated with reduced metastasis and invasion, making it an ideal marker for the identification of motile epithelial cells.1 Epithelial tumors are highly heterogeneous masses, where individual cells within the same tumor exist in states ranging from proliferative to quiescent, hypoxic to oxygenated and rigid to motile. It is not surprising that these tumors easily evade therapeutic agents that target a specific cellular phenotype. For instance, agents targeting angiogenesis have a low impact on hypoxic avascular areas of the tumor. Further, resistance to chemotherapeutic agents has been reported in cells that have undergone EMT.2 A correlation between levels of EMT regulator Snail, a known repressor of Ecad expression and genes involved in chemoresistance, has been reported in head and neck squamous cell carcinoma.3 In fact, EMT not only contributes to chemoresistance, but also to tumor progression. Thus, strategies that target mesenchymal-like tumor cells with a metastatic potential are critical to improving outcome. Basu and colleagues have identified a novel strategy to target mesenchymal-like cell populations within squamous cell carcinoma. The authors separated the cells based up on their Ecad levels. Cells expressing high levels of Ecad have a distinct epithelial morphology, while those with low Ecad are akin to mesenchymal cells. Segregation of the cell types facilitated studies on the sensitivity of each population to chemotherapy and molecular targeted agents. Interestingly, while Ecad high cells were sensitive to cisplatin, Ecad low cells were resistant to the drug, corroborating previous reports on the chemoresistant properties of mesenchymal-like cells.4 In order to target the mesenchymal tumor cells, the authors built upon previous work in breast carcinomas, where CD44+CD24- tumor stem cells were targeted with a potassium ionophore antibiotic salinomycin.5 The CD44+CD24- tumor stem cells were reported to have mesenchymal properties as a result of EMT.6 Ecad low cells, mesenchymal cells resistant to cisplatin, were effectively targeted with salinomycin. In vitro, the antitumor effects of salinomycin were not restricted to mesenchymal tumor cells alone, but were also observed in Ecad high epithelial tumor cells. However, xenografts established from primary HNSCC treated with salinomycin had a significant depletion in vimentin-positive tumor cells, indicating that the drug either mitigated EMT or selectively abrogated the mesenchymal-like tumor cells. Primary tumor-derived xenografts serve as excellent models that closely recapitulate the histological and molecular features of the primary tumor.7 Although combining salinomycin with cisplatin did not result in enhanced antitumor effects in vitro, in a recent study, salinomycin enhanced the effects of doxorubicin and etoposide by increasing DNA damage in breast, liver and uterine cancer cells.8 In another study, combining cisplatin with a natural compound Lupeol reported to reverse EMT, induce synergistic antitumor effects and reduce metastasis in an orthotopic HNSCC model.9 Thus, strategies involving agents that target mesenchymal-like tumor cells curtailing tumor growth and progression holds tremendous therapeutic potential. The study by Basu and colleagues demonstrates that targeting mesenchymal-like tumor cells is feasible in HNSCC, opening the door to further investigations into the development of new drugs targeting metastatic cell populations.