Abstract
Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are often undervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating on exciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions.
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Abbreviations
- TME:
-
Tumor microenvironment
- TAM:
-
Tumor-associated macrophages
- CAF:
-
Cancer-associated macrophages.
- ITH:
-
Intratumor heterogeneity
- ECM:
-
Extracellular matrix
- CSCs:
-
Cancer stem cells
- Hh:
-
Hedgehog
- HIF:
-
Hypoxia-inducible factor
- P4HA:
-
Prolyl 4-hydroxylase
- LOX:
-
Lysyl oxidase
- LOXL:
-
Lysyl oxidase-like proteins
- PLOD:
-
Procollagen-lysine, 2-oxoglutarate 5-dioxygenase
- ITGA:
-
Integrin subunit alpha
- FN:
-
Fibronectin
- MDR:
-
Multidrug resistance
- CIN:
-
Chromosomal instability
- MSI:
-
Microsatellite instability
- EMT:
-
Epithelial–mesenchymal transition
- MMP:
-
Matrix metalloproteinase
- PDGF:
-
Platelet-derived growth factor
- PI3K:
-
Phosphatidylinositol 3-kinase
- MDSC:
-
Myeloid-derived suppressor cells
- TNF-α:
-
Tumor necrosis factor α
- VEGF:
-
Vascular endothelial growth factors
- CCL2:
-
Chemokine C–C motif ligand 2
- TEC:
-
Tumor endothelial cells
- CTCs:
-
Circulating tumor cells
- ADC:
-
Antibody‒drug conjugates
- ICI:
-
Immune checkpoint inhibitors
- ACT:
-
Adoptive cell therapy
- TIL:
-
Tumor-infiltrating lymphocytes
- tgTCR:
-
Transgenic T-cell receptor
- CAR T:
-
Chimeric antigen receptor-modified T cells
- Flt3L:
-
Fms-like tyrosine kinase 3 ligands
- PSCA:
-
Prostate stem cell antigen
- COL4A1:
-
Collagen type IV alpha 1
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Imodoye, S.O., Adedokun, K.A. & Bello, I.O. From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy. Histochem Cell Biol 161, 299–323 (2024). https://doi.org/10.1007/s00418-023-02258-6
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DOI: https://doi.org/10.1007/s00418-023-02258-6