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Evolving concepts of tumor heterogeneity.

Zellmer VR, Zhang S - Cell Biosci (2014)

Bottom Line: This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype.Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment.In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Science, Harper Cancer Research Institute, University of Notre Dame, A130 Harper Hall, Notre Dame, IN 46556 USA.

ABSTRACT
Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

No MeSH data available.


Related in: MedlinePlus

Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.
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Fig2: Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.

Mentions: Tumor cells undergo a series of genetic events that contribute to genomic instability throughout tumor progression (Figure 2A). However, the specific mechanisms and precise order in which they occur have yet to be elucidated [21]. Studies have pursued these mechanisms and found that the rate at which mutations occur in somatic cells is insufficient to cause the striking number of mutations present in cancer genomes. Over the past few decades, a ‘mutator’ hypothesis tumor evolution has emerged, speculating that a mutator phenotype characterized by genomic instability drives multi-step carcinogenesis and explaining the mutation rate discrepancy observed in normal and malignant cells [22]. This concept was initially described in Nowell’s paper where he attributes the high number of mutations in cancer genomes to waves of clonal selection [5, 23]. Studies in bacteria and yeast imply mutator mutations confer a selective growth advantage on cells harboring these acquired mutations [24, 25]. The current mutator hypothesis speculates that a small number of ‘driver’ alterations exist and, once acquired by somatic mutation, confer the cancer phenotype; however, seemingly insignificant ‘passenger’ mutations result via mechanisms yet to be elucidated [26]. McFarland et al. challenged this with stochastic simulation of tumor evolution and reasoned that, though individually weak, the cooperative burden of small-scale accumulated passenger mutations has a present role in tumor progression, and may be the cause for complex oncological events that remain unanswered by the driver-centric model [27].Figure 2


Evolving concepts of tumor heterogeneity.

Zellmer VR, Zhang S - Cell Biosci (2014)

Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4417538&req=5

Fig2: Tumor evolution and compositional heterogeneity. A, Evolution drives heritable heterogeneity and subsequent outgrowth of malignant clones. Selection pressures from the local microenvironment (e.g. hypoxia, secretion of growth-inhibiting factors, chemotherapeutic agents, etc.) challenge tumor cell survival, often resulting in cell death in early cancer initiation. In order to survive these in a given tissue niche, cancer cells must acquire mutations that promote survival and tumor formation with regard to spatiotemporal context. Robust cells capable of surviving multiple selection events acquire proliferative advantages, eventually resulting in tumor progression and evidence of genetic heterogeneity within a tumor. B, Snapshots of natural selection events within the TME paint a heterogeneous portrait of tumor composition in a spatial context. The TME refers to both the tumor and its local environment of diverse resident and migratory cell types. 1) Infiltrated immune cells shape the tumor development; 2) Tumor stromal cells interact with tumor cells and change the local cancer stem cell niche; 3) Bi-directional plasticity between stem-like cancer cells and tumor cells. 4) Disseminated tumor cells.
Mentions: Tumor cells undergo a series of genetic events that contribute to genomic instability throughout tumor progression (Figure 2A). However, the specific mechanisms and precise order in which they occur have yet to be elucidated [21]. Studies have pursued these mechanisms and found that the rate at which mutations occur in somatic cells is insufficient to cause the striking number of mutations present in cancer genomes. Over the past few decades, a ‘mutator’ hypothesis tumor evolution has emerged, speculating that a mutator phenotype characterized by genomic instability drives multi-step carcinogenesis and explaining the mutation rate discrepancy observed in normal and malignant cells [22]. This concept was initially described in Nowell’s paper where he attributes the high number of mutations in cancer genomes to waves of clonal selection [5, 23]. Studies in bacteria and yeast imply mutator mutations confer a selective growth advantage on cells harboring these acquired mutations [24, 25]. The current mutator hypothesis speculates that a small number of ‘driver’ alterations exist and, once acquired by somatic mutation, confer the cancer phenotype; however, seemingly insignificant ‘passenger’ mutations result via mechanisms yet to be elucidated [26]. McFarland et al. challenged this with stochastic simulation of tumor evolution and reasoned that, though individually weak, the cooperative burden of small-scale accumulated passenger mutations has a present role in tumor progression, and may be the cause for complex oncological events that remain unanswered by the driver-centric model [27].Figure 2

Bottom Line: This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype.Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment.In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Science, Harper Cancer Research Institute, University of Notre Dame, A130 Harper Hall, Notre Dame, IN 46556 USA.

ABSTRACT
Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

No MeSH data available.


Related in: MedlinePlus