!: Saving Role of Notch-1 signaling in adenocarcinoma of the lung. purchase
Lung cancers are the most deadly malignancies in the U.S.. Adenocarcinoma of the lung (ACL) represents about 50% of all lung cancer cases in the Western world. ACL is relatively frequent in people who have never smoked, and there are evidences suggesting that these cases cannot be addressed with smoking eradication policies only. Current chemotherapy of ACL is in large part palliative. Therefore it is critical to find new targets to treat such a deadly disease. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to cancer. However, little is known about its role in lung cancer. In this study I have analyzed the role played by Notch signaling in lung cancer with a special emphasis on ACL. My results showed an apparent tumor suppressor role for Notch signaling in ACL when studied in vitro. However, these results did not reflect some parameters that I measured in ACL tumor biopsies. To solve this apparent paradox I studied whether the tumor microenvironment played a significant role in determining the biological effects of Notch signaling in ACL. I found that ACL is profoundly affected by hypoxia, the microenvironmental condition most common in ACL. I found that Notch-1 confers critical survival signals to ACL cells under hypoxia. This appears to be mediated through the Akt, Bcl2-A1 and caspase-1 activities. More importantly, I found that targeting Notch-1 activation using a small chemical inhibitor represents a very promising and novel therapeutic strategy for the treatment of ACL cells residing in hypoxic environments. These latter malignant cells are those responsible for cancer resistance to standard chemotherapy, cancer recurrence and cancer stem cell renewal. The hypothesis that targeting Notch through chemical inhibitors may represent a major improvement in chemotherapy of ACL patients is now being tested in our laboratory in preclinical settings.
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