ABC transporters are highly conserved and represent a major protective mechanism for barrier tissues as well as adult tissue stem cells (1
). Survival of tissue stem cells is essential to tissue maintenance and repair, and constitutive MDR activity is thought to be one of several protective mechanisms by which normal tissue stem cells guard themselves form from toxic insults, including those resulting from damage by chemotherapeutic agents (10
). Moreover, in the absence of tissue stem cell specific markers, the activity of these transporters has been exploited to obtain enriched populations of tissue stem cells (5
); the efflux or exclusion of fluorescent MDR substrates such as rhodamine 123 (ABCB1 substrate, R123dull/dim phenotype) and Hoechst33342 (ABCG2 and to a lesser degree ABCB1 substrate, Side Population (SP) phenotype) are frequently used in fluorescence activated cell sorting of hematopoietic and non-hematopoietic tissue stem cells.
The unique insight which we derive from the study of adult tissue stem cells and bone marrow derived stem cells (5
) is that drug resistance, mediated in large part by ABC transporters, is a normal physiologic self-protective mechanism, which we hypothesize is retained by the nascent neoplasm upon transformation of the tissue stem cell (10
). The notion that the cancer-initiating cell may have constitutive drug resistance predicts the persistence of a therapy resistant stem cell-like fraction following apparently successful cytotoxic cancer therapy resulting in the marked shrinkage or even disappearance of measurable tumor. Therapies that target proliferating cells, enzymes, growth receptors, adherence molecules, or signaling molecules in metabolically active cells may be highly effective at debulking tumors and dispatching tumorigenic cells without stem cell like properties, but they will consistently fail to eradicate the rare tumor cell fraction that shares protective mechanisms with their normal counterparts.
The cancer stem cell hypothesis attempts to explain the origin of cancer and identifies the cancer initiating cell as a transformed tissue stem cell. However, human cancers are heterogeneous and it is not always possible to apply a rigorous classification into stem, progenitor and mature compartments on the basis of differentiation marker expression and morphology. In normal adult tissues, stem cells are small resting undifferentiated cells which are confined to anatomic niches in which they are protected from toxic insults by both interaction with niche cells and by intrinsic mechanisms such as MDR transporter activity and detoxifying enzymes. When they are driven into proliferation, they replicate asymmetrically, giving rise to a stem cell daughter which remains in the niche, and a progenitor daughter (or transit amplifying cell) which migrates out of the niche, proliferates and efficiently gives rise to mature post mitotic cells with tissue specific characteristics. In doing so, the progenitor and its progeny progressively lose the markers of “stemness” (including self renewal and self-protection) as they gain tissue specific markers. However, there are variations on this theme, in which cells with mature function, such as hepatocytes, given appropriate stimuli, can revert to progenitor status and mediate tissue regeneration. It is also worthwhile to distinguish between three partially overlapping roles of tissue stem cells. The first role, organogenesis, is largely complete at birth, with the exception of the breast and prostate, which develop at puberty under hormonal influences. The second role, tissue maintenance, is a continuous process that proceeds at a rapid pace in some organs (skin, gut, blood) and at a glacial pace in others (nerves). Finally, adult tissue stem cells mediate tissue repair after injury, a function that is better developed in some organs (liver, blood) than in others (nerve). Whatever the role, the adult tissue stem cell is characterized by its anatomic location, and ability to self-replicate, self-protect, and give rise to further differentiated progeny of high proliferative capacity.
Returning to the cancer stem cell hypothesis, a strong analogy can be made between tumor growth and normal tissue growth in that: 1) The majority of tumor cells are post mitotic (non tumorigenic); 2) In order to be tumorigenic, at least a fraction of cells must be capable of sustained self-renewal (i.e. not loose proliferative capacity as a function of proliferative history); 3) In order to survive the toxic insults of therapy, a proportion of cells must retain or develop self-protective mechanisms (drug transport and metabolism). shows a schematic representation of the cancer stem cell hypothesis. A mutated stem cell is shown at the top of the chain, characterized by its resting protected state. These cells and their progeny, active, tumorigenic progenitor cells have already departed from the normal schema, as they retain the capacity for self renewal, as well as the ability to dedifferentiate into resting a resting protected phenotype. These last two points come from our experimental data showing that purified large, stem/progenitor marker positive (CD90), proliferating, MDR negative tumor cells are tumorigenic at very high frequency, and give rise to tumors as heterogeneous as those from which they were purified, including a small proportion of stem/progenitor marker+, MDR+ resting cells (13
). In this report we will further explore the expression of stem and progenitor cell markers and MDR activity in lung cancer and normal lung tissue, with emphasis on reconciling the cancer stem cell paradigm with both low and high grade malignancies.
The cancer stem cell hypothesis attempts to explain the origin of cancer and identifies the cancer initiating cell as a transformed tissue stem cell