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Review
. 2010 Jun 15;16(12):3121-9.
doi: 10.1158/1078-0432.CCR-09-2933. Epub 2010 Jun 8.

The difficulty of targeting cancer stem cell niches

Mark A LaBarge  1
Affiliations
Review

The difficulty of targeting cancer stem cell niches

Mark A LaBarge. Clin Cancer Res. .

Abstract

Normal stem cell niches typically are identified by their distinctive anatomical features and by association with tissue-specific stem cells. Identifying cancer stem cell (CSC) niches presents a special problem because there are few if any common anatomical features among tumors, and the physical phenotypes that reportedly describe the CSCs as entities may be subject to the host's microenvironment, sex, and tumor stage. Irrespective of a niche's location, the occupant's phenotype, or the precise molecular composition, all niches must do basically the same thing: maintain the activities in a stem cell that define it as such. Therefore, a potentially successful strategy, both for elaborating a molecular and cellular portrait of a CSC niche, and for therapeutically targeting them, is to identify components in the tumor microenvironment that are required for maintaining the functions of self-renewal, differentiation, and quiescence in the face of cytotoxic therapeutic regimens.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed

Figures

Fig. 1
Fig. 1
The basic concept of a stem cell niche. Niches are special microenvironments that maintain, or even endow cells with, stem cell activity. Cell-cell communication through adherens junctions, cell-ECM communication through integrins, paracrine, juxtacrine, and hormonal signaling, mechanical sensing of physical and geometric constraints, and integration of neural signals are all coordinated to enforce quiescence (red signals) and to tightly regulate self-renewal (green signals).
Fig. 2
Fig. 2
Loss of predictable tissue morphology in tumors presents challenges to identifying the CSC niche. A and B, stem cell niches are clearly identifiable in normal tissues. A, a cross-section of normal human mammary gland terminal duct shows the exquisite bilayered architecture of the tissue. The stem cells are nestled inside their suprabasal niche and express both keratins (K)14 and K19 (yellow, inset). They give rise to their differentiated progeny, the K14-expressing myoepithelial (green) and K19-expressing luminal cells. B, a depiction of the Drosophila germarium stem cell niche showing the stem cells (GSC, green) adjacent to the cap cells (CC, light blue). The stem cells give rise to the more differentiated progeny at their right. C and D, normal architecture is quickly lost in early stages of tumorigenesis. C, a cross section of human mammary duct, which is stricken with ductal carcinoma in situ, a noninvasive form of breast cancer that is thought to precede more invasive forms. D, shows a tumor laden germarial tip. The tumor in this case was derived from differentiation-defective bcgn mutant stem cells that outcompeted the normal stem cells for niche occupation due to upregulated E-cadherin expression, and subsequently filled the germarium with their mutant progeny. In both tumors, it is difficult or impossible to determine which of the tumor cells are the CSCs based on tissue morphology. A was adapted with permission from Villadsen et al. (71). B and D are adapted with permission from Jin et al. (1). C is reproduced from http://commons.wikimedia.org/wiki/File:DCIS.jpg
Fig. 3
Fig. 3
Modulating pathways involved in maintenance of the mammary stem cell state in malignant mammary epithelial cells may effectively halt disease progression. A, malignant mammary epithelial cells, HMT3522-T4-2 (T4-2), were embedded in Matrigel and grown for 72 hours in presence of the gamma secretase inhibitor (GSIxx), which blocks activation of the entire Notch pathway. Untreated cells formed disorganized and apolar colonies that do not growth-arrest, which appear characteristically rough under phase microscopy, whereas GSIxx treated cells growth-arrest after a few divisions and form smooth acini. B, GSIxx imposed the phenotypic reversion in a dose-dependent manner. C, representative confocal images of the hemispherical optical section from acini in three-dimensional culture. Basal polarity marker, integrin α6 (red), is expressed on all cell surfaces in colonies of the untreated malignant cells, whereas it was only expressed at the basal surfaces of the phenotypically reverted acini grown in presence of GSIxx. D, image analysis of three-dimensional cultures using NIH ImageJ was used to generate composite images, shown as probability of distribution heat maps, of integrin α6 distribution that occurs most frequently among the acini in a given three-dimensional culture condition. E, left side, Integrin α6 distribution maps are shown for cultures of GSIxx treated T4-2 cells, as well as cultures that were infected with retroviruses expressing small hairpin RNA (shRNA) to knock down each of the four Notch receptors (Notch1–4). E, right side, Bar graphs showing the impacts of each shRNA on apoptosis, via TUNEL stain, and proliferation, via Ki67 stain. Targeting different notch receptors elicited distinct phenotypes: Notch 1 and 2 shRNAs imposed normal polarity and had modest impact on apoptosis or proliferation, whereas Notch 3 and 4 shRNAs had little impact on restoring normal polarity and had a large impact on the apoptotic and proliferative phenotypes. (For more reading on the concept of phenotypic reversion see refs. 66, 72).
Fig. 4
Fig. 4
Do CSCs and their niches evolve in parallel with tumor progression? A depiction of a hypothetical bilayered, lumen-containing epithelial tissue (e.g., mammary gland). Normal stem cells (solid blue circles) are located inside their suprabasal niche, sandwiched between two differentiated cell types (represented by open rectangles and ovals). A differentiation defective CSC may outcompete the normal SCs for position within the niche. Because the CSCs are not bound by usual constraints on self-renewal, their mutant daughters begin to populate the tissue until normal organization and architecture are lost. Either the original CSC evolves, or the tumor microenvironment imposes stem cell-like properties onto random tumor cells to generate de novo CSCs, which accommodates tumor progression and eventual metastatic dissemination.
See this image and copyright information in PMC

References

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