Epigenetics and the plasticity of differentiation in normal and cancer stem cells

Lotem, Joseph; Sachs, Leo

doi:10.1038/sj.onc.1209816

Cited by 82 publications

(58 citation statements)

References 231 publications

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“…The BMDCs that home to the tumor neovasculature and premetastatic sites could be used as "magic bullets," delivery vehicles for anti-cancer strategies (Arafat et al 2000). The feasibility of integrating a suicide gene into BMderived progenitors to reduce tumor size and vascularity has already been confirmed in several animal studies (Komarova et al 2006;Lotem and Sachs 2006). Not only HPCs and EPCs, but also fibroblasts and stromal progenitors that migrate to tumor sites might prove particularly useful as carriers of oncolytic adenoviruses or as direct targets of "activated" or genetically altered stromal cells.…”

Section: Potential Therapeutic Implicationsmentioning

confidence: 88%

Migratory neighbors and distant invaders: tumor-associated niche cells

Wels

Kaplan²,

Rafii³

et al. 2008

Genes Dev.

356

302

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The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.Understanding the complex biological networks at play in metastasis requires a precise detailing of the molecular and cellular pathways involved in local and systemic migration. The long prevailing model of invasion and metastasis has focused on the adhesive and migratory capabilities that are intrinsic to tumor cells (Hanahan and Weinberg 2000). Meanwhile, we are becoming increasingly aware that tumors are composed of genetically altered malignant cells along with a heterogeneous population of stromal cells, whose dynamic interactions can profoundly enhance tumor progression and metastasis. Through the production of chemokines, growth factors, and matrix-degrading enzymes (Table 1), supportive cells-including fibroblasts, immune cells, and bone marrow (BM)-derived stem and progenitor cells-support blood vessel formation, break down basement membrane barriers, and attract tumor cells to distant sites. Tumor cells are constantly giving instructions, not only by direct cell-cell interactions, but also by secreted factors that "activate" normal host cells at both proximal and distal sites to migrate, eventually developing permissive niches that, in return, promote tumor cell survival and proliferation. The focus of this review is on the cellular constituents of the primary and metastatic tumor microenvironments, with emphasis on their migratory pathways. We hope to convey that the tumor and host cell interaction is truly reciprocal; while host cells may support tumor cells, tumor cells in turn modulate the microenvironments within which they reside. Furthermore, we highlight that cancer is a systemic disease, encompassing collective cell movements of tumor and stromal cells that are a prerequisite for tumor cell invasion and metastasis. Intrinsic tumor cell migratory capabilitiesInherent to the metastatic process is the capability of tumor cells to migrate through connective tissue barriers comprising cell-cell adherent junctions, basement membranes, and interstitial tissue stroma. This intrinsic migratory behavior is highly dependent on the interplay between adhesive and proteolytic activities. Tumor cell down-regulation of proteins mediating cell-cell interactions, such as cadherins, leads to changes in cell signaling, actin-based cytoskeletal structure, and eventual dissociation from n...

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Section: Potential Therapeutic Implicationsmentioning

confidence: 88%

Migratory neighbors and distant invaders: tumor-associated niche cells

Wels

Kaplan²,

Rafii³

et al. 2008

Genes Dev.

356

302

View full text Add to dashboard Cite

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“…Indeed, inhibitors of DNA methyltransferases and/or histone deacetylases have been shown to induce CSC differentiation that bypasses cancer-associated genetic abnormalities (119). In recent clinical findings in patients with locally advanced breast cancer, a therapeutic regimen consisting of the demethylating agent hydralazine and the histone deacetylase inhibitor magnesium valproate followed by doxorubicin and cyclophosphamide therapy resulted in a trend toward improved clinical outcome compared with doxorubicin and cyclophosphamide therapy alone (124).…”

Section: Figurementioning

confidence: 99%

“…Potential strategies that induce quiescent CSCs to differentiate into more mature tumor cells include activation of distinct signaling pathways, such as morphogen-driven signaling cascades (66); alteration of gene expression profiles using microRNAs (miRNAs; ref. 96); and epigenetic differentiation therapy (119,120). Piccirillo et al have harnessed BMP signaling to differentiate CSCs in experimental models of human glioblastoma (66).…”

Section: Figurementioning

confidence: 99%

The therapeutic promise of the cancer stem cell concept

Frank¹,

Schatton²,

Frank³

2010

J. Clin. Invest.

565

486

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Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for those malignancies that are currently refractory to conventional anticancer agents directed predominantly at tumor bulk populations.

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“…Finally, plasticity in CSCs and their progeny will further contribute to cancer cell and CSC heterogeneity [118], which I discuss below.…”

Section: Csc Heterogeneitymentioning

confidence: 99%

Understanding cancer stem cell heterogeneity and plasticity

2012

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Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.

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Epigenetics and the plasticity of differentiation in normal and cancer stem cells

Cited by 82 publications

References 231 publications

Migratory neighbors and distant invaders: tumor-associated niche cells

Migratory neighbors and distant invaders: tumor-associated niche cells

The therapeutic promise of the cancer stem cell concept

Understanding cancer stem cell heterogeneity and plasticity

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