Tumorigenic stem and progenitor cells: implications for the therapeutic index of anti-cancer agents.

Cancer recurrence following response to therapy suggests that resistant cells lay dormant and subsequently reactivate. The cancer stem cell paradigm explains why tumors typically consist of a large therapy sensitive compartment, and a smaller compartment with profound intrinsic resistance. Here we examine co-expression of tissue stem cell markers (CD90, CD117, CD133) and cytokeratin in previously untreated non-small cell lung cancer (NSCLC). In normal lung (NL), we assign a provisional phenotype to resting stem cells (low scatter, cytokeratin-and either CD90(dim)/CD133+, or CD117+). Progenitors share this phenotype but are morphologically complex, downregulating CD90 as they gain cytokeratin. This pattern is retained in well-differentiated NSCLC, but is deranged in poorly-differentiated NSCLC, the most common pattern being overexpression of cytokeratin on stem/progenitors. Stem cells and progenitors are present at approximately 1% and 10% in NL and NSCLC, respectively. Constitutive multiple drug resistance (MDR) was present in approximately 6% of well-differentiated and approximately 50% of poorly differentiated tumors. We hypothesize that among the minority of tumor cells capable of propagating a tumor, only those that self-protect survive therapy. Of surviving cells, only those which, like normal stem cells, are predominantly resting, cause recurrence after remission. The therapeutic index of antineoplastics thus becomes one of sensitivity of cancer and normal stem cells, which are protected by the same mechanisms.