Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution
Abstract
Simple Summary
Abstract
1. Introduction: Intra-Tumour Heterogeneity Infers Tumour Evolution
2. Challenges in Understanding Cancer Evolution
3. Models of Tumour Evolution
3.1. Origins of Cancer—A Founder Cell
3.2. Linear and Neutral Evolution in the Context of Cancer
3.3. Branching Evolution, Parallel Evolution and Convergence
4. Non-Genetic Mechanisms in Cancer Progression and Adaptation
4.1. Molecular Basis of Non-Genetic Heterogeneity
4.2. Drug-Tolerant Phenotypic States
4.3. EMT at the Basis of Tumour-Initiating Phenotype and Tumour Dissemination
4.4. Phenotypic Plasticity
5. Cancer Ecosystem
5.1. Microenvironment—The Main Source of Selective Pressure
5.2. Extracellular Matrix in Tumour Progression
5.3. Immune Cell Component of the Tumour Microenvironment
5.4. Niche Construction
5.5. Sub-Clonal Cooperation
5.6. Microbiome
6. Therapeutic Avenues—Lessons from Cancer Evolution
6.1. Targeting Genetic Heterogeneity
6.2. Targeting Non-Genetic Heterogeneity
6.3. Targeting the Tumour Microenvironment
7. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Appendix A.1. Allele Specific Gene Expression in Cancer Initiation and Progression
Appendix A.2. Molecular Basis of EMT and MET
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Component of the Tumour Microenvironment | Example | Impact on Cancer Biology | References |
---|---|---|---|
Increased stiffness of ECM | Promotes translocation of EMT-regulating transcription factors into the nucleus and drives EMT in breast cancer and PDAC. | [160,161] | |
PLX4720 mediated ECM remodelling | Triggers increased integrin β1/FAK/Scr signalling in BRAF-mutated melanoma cells. This is followed by ERK signalling activation that results in the establishment of resistance to PLX4720. | [162] | |
ECM and other non-cellular components | Vemurafenib mediated fibronectin deposition | Results in increased AKT/PI3K activation, which abrogates the cytotoxic response to the BRAF inhibitor. | [163] |
Hypoxia | Activates gene expression programs that facilitate cancer cell survival, induce invasive growth, reduce immune responses and promote vascularization in hypoxic regions. Hypoxia is associated with increased genomic instability in different type of tumours. | [164,165] [166] | |
Inflammatory environment | May promote tumour growth directly by inducing cancer cell proliferation, or indirectly by down-modulating the immune response, activating tumour-promoting innate immunity signalling, impairing the induction of angiogenesis and removing constrains in tissue remodelling. Induces the expression of tumour promoting factors. | [167] [168,169] | |
Monocytes and macrophages | Production of TNF-α by a macrophage population triggers MITF expression, resulting in cancer cell resistance to MAPK-inhibitors. | [170] | |
Immune cells and other cellular components | Macrophages | Macrophage-enriched subtype of triple negative breast cancer displays sensitivity to immunotherapy. | [171] |
Neutrophils | Neutrophil-enriched subtype of triple negative breast cancer shows resistance to immunotherapy. | [171] | |
Cancer associated fibroblasts | Extensive deposition of extra cellular matrix that causes desmoplasia. | [158] | |
Marrow-derived hematopoietic progenitor cells | Upon recruitment to distant pre-metastatic, sites these cells modify the local microenvironment to promote micrometastatic lesions. | [172,173] | |
Pro-metastatic cooperation | In polyclonal breast cancer models, low-represented subpopulations expressing IL-11 (interleukin 11) and FIGF (Fos-induced growth factor) can drive proliferation in other sub-clones and promote metastasis. | [174,175] | |
Tumorigenic cooperation | A bi-clonal breast cancer model containing genetically distinct luminal and basal sub-clones is highly tumourigenic when transplanted into wild type mice, while monoclonal populations fail to cause tumours. | [176] | |
Sub-clonal cooperation | Growth promoting cooperation | In a glioblastoma multiforme mouse model, a minor population that harbours mutant EGFR can promote growth of EGFR wild-type cells within the same tumour. | [177] |
Drug resistance | Colorectal cancer cells resistant to EGFR blockade express TGF-α that sustains EGFR/ERK pathways and thus protects their sensitive counterparts from EGFR inhibitors. | [178] | |
“Self-seeding” | Circulating tumour cells derived from metastatic sites can colonize their tumours of origin and promote tumour growth. | [179] | |
Cancer initiation and progression | Heliobacter pylori can cause gastric cancer. Fusobacterrium spp is associated with colorectal adenocarcinoma and colon cancer. Increased abundance of Escherichia coli is observed in colon cancer patients. Malassezia spp residing within PDAC contributes to tumour progression. | [180,181,182] | |
Drug resistance | Intra-tumour bacteria—Gammaproteobacteria—can metabolize a chemotherapeutic agent, gemcitabine, into its inactive form, thereby granting tumour resistance in colon cancer models. | [183] | |
Microbiome | Modulation of cancer immune response | Upon cyclophosphamide treatment, a defined set of Gram-positive bacteria species translocates from the small intestine into secondary lymphoid organs where it promotes the generation of “pathogenic” T helper 17 (pTH17) cells and memory TH1 immune mediated response. | [184] |
Shaping the intra-tumour microenvironment | The specific microbiome of PDAC patients may increase the abundance of CD3+ and CD8+ T cells and granzyme B+, which correlates with immune activation in tumours of long-term survivors (LTS) as compared to short-term survivors (STS). | [185] |
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Shlyakhtina, Y.; Moran, K.L.; Portal, M.M. Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution. Cancers 2021, 13, 1380. https://doi.org/10.3390/cancers13061380
Shlyakhtina Y, Moran KL, Portal MM. Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution. Cancers. 2021; 13(6):1380. https://doi.org/10.3390/cancers13061380
Chicago/Turabian StyleShlyakhtina, Yelyzaveta, Katherine L. Moran, and Maximiliano M. Portal. 2021. "Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution" Cancers 13, no. 6: 1380. https://doi.org/10.3390/cancers13061380
APA StyleShlyakhtina, Y., Moran, K. L., & Portal, M. M. (2021). Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution. Cancers, 13(6), 1380. https://doi.org/10.3390/cancers13061380