Cancer Stem Cells in Tumor Heterogeneity

Pietras, Alexander

doi:10.1016/b978-0-12-387688-1.00009-0

Cited by 72 publications

(60 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Two models to explain intratumoral heterogeneity have been proposed. The clonal evolution model asserts that different subclones arise from a single progenitor as a consequence of molecular changes followed by selection for dissimilar microenvironments within a tumor (1). By contrast, the cancer stem cell model contends that a small population of stem cells originating from a single progenitor is responsible for tumor maintenance but the progeny can differentiate in several diverse ways (1).…”

mentioning

confidence: 99%

Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

Thliveris

Schwefel

Clipson³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues.colon cancer | spatial statistics | clonal interactions | mouse model T umors are often heterogeneous with respect to several distinguishable properties, including differentiation state, proliferation rate, metastatic potential, and therapeutic response. Two models to explain intratumoral heterogeneity have been proposed. The clonal evolution model asserts that different subclones arise from a single progenitor as a consequence of molecular changes followed by selection for dissimilar microenvironments within a tumor (1). By contrast, the cancer stem cell model contends that a small population of stem cells originating from a single progenitor is responsible for tumor maintenance but the progeny can differentiate in several diverse ways (1). A key assumption in both models is that tumors are derived from a single progenitor.Evidence is steadily accruing that intestinal tumors are often polyclonal rather than monoclonal (2). Merritt et al. (3) demonstrated that hereditary tumors in the mouse intestine are often derived from multiple progenitors. In this study, aggregation chimeras were generated by fusing embryos carrying the Min allele of the Adenomatous polyposis coli gene (Apc Min/+ ) to embryos carrying Min and the Rosa26 lineage marker (Apc Min/+ R26 + ). Clonal structure was assessed in histologic sections of tumors stained for the lineage marker. A significant number (8%) of early adenomas were heterotypic, being composed of cells from the two different embryos. Using a similar approach, Thliveris et al. (4) demonstrated that carcinogen-induced tumors in mice are also derived from multiple progenitors. In both studies, the intestines consisted of small blue and white patches. This chimeric pattern increases the power to ...

show abstract

mentioning

confidence: 99%

Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

Thliveris

Schwefel

Clipson³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It is critical that the neurospheres that will form over 1-3 weeks (Figures 1B-E) are transferred to fresh flasks, to separate from differentiated tumor cells and debris. 19,20 . In addition to being vital for generating patient-specific GBM animal models, the neurosphere cultures are also valuable for in vitro studies such as alteration in cell signaling and gene expression in response to growth factors, hypoxia, and pharmacological agents 11,21 .…”

Section: Discussionmentioning

confidence: 99%

Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in Clinically Relevant Animal Models and 3D Immunochemistry

Hasselbach

Irtenkauf

Lemke

et al. 2014

JoVE

View full text Add to dashboard Cite

Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor.Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies.

show abstract

“…Eradicating the entire stem cell population at a given point does not necessarily lead to a cancer cure, as implicated in the classical stem cell model, but stem cells could be readily replenished from more differentiated progeny [7,45]. Nevertheless, it is still not completely certain, to what extend the EMT-induced dedifferentiation into cancer stem cells really takes place.…”

Section: Abcb5mentioning

confidence: 98%

The dynamics of cancer stem cells

Hatina

2012

neo

View full text Add to dashboard Cite

With the formulation of the hierarchical model of tumor cell organization, cancer stem cells came to the forefront of cancer biology. As the only self-renewing tumor cells, they were made responsible for continuous tumor growth and their intrinsic self-protection ability was postulated to underlie cancer therapy resistance and/or recurrence. The concept of migrating cancer stem cells extended the relevance of the hierarchical cancer cell model to issue of cancer progression, with the crucial experimental evidence being provided by the demonstration that epithelial mesenchymal transition can convey stemness. Accordingly, cancer stem cells probably represent a highly dynamic cell population continuously differentiating and being continuously replenished by processes like mesenchymal epithelial transition and epithelial mesenchymal transition, respectively. Consequently, from the point of view of therapeutic targeting, cancer stem cells obviously do not represent a fixed target population any longer. Understanding the dynamic nature of cancer stem cells is thus essential not only for the progress in our understanding of basic cancer biology, but also from the therapeutic perspective.

show abstract

Cancer Stem Cells in Tumor Heterogeneity

Cited by 72 publications

References 116 publications

Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors

Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in Clinically Relevant Animal Models and 3D Immunochemistry

The dynamics of cancer stem cells

Contact Info

Product

Resources

About