Targeting the Tumor Microenvironment to Overcome Resistance to Therapy

  • Bessi Qorri
  • Myron R. SzewczukEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 20)


Recent advancements in cancer research have led to a deeper understanding of tumor biology and uncovered the crucial role of the tumor microenvironment (TME) in promoting multistage tumorigenesis. As such, it is widely accepted that the tumor microenvironment is plastic and can shape a tumor’s response to therapy and subsequently contribute to the development of resistance. Consequently, therapeutic options for cancer are now transitioning from traditional cancer cell-centric approaches to holistic approaches that incorporate the tumor microenvironment and its complex interactions. However, in order to optimize such therapies and mitigate the challenge of acquired resistance, it is imperative that we understand the complexities of the tumor microenvironment. Doing so will shed light on the interactions between the extracellular matrix, cytokines, growth factors, integrins, proteases, cancer-associated fibroblasts, myeloid cells, tumor-infiltrating lymphocytes, aberrant neovasculature, and exosomal transporters, all of which have been implicated in contributing to the development of resistance to therapy. Clinical success requires cancer therapies that are capable of circumventing multistage tumorigenesis, including aberrant growth factor receptor activation, tumor neovascularization, chemoresistance, immune-mediated tumorigenesis, and the development of metastatic disease. We describe the role of mammalian neuraminidase-1 in complex with matrix metalloproteinase-9 and G protein-coupled receptors tethered to receptor tyrosine kinases and Toll-like receptors in multistage tumorigenesis upending cancer resistance. Here, we highlight an innovative and promising therapy that simultaneously targets many of the components within the TME to overcome acquired resistance.


Acquired resistance Extracellular matrix Angiogenesis Inflammation Hypoxia Tumor heterogeneity Multistage tumorigenesis Multimodal therapy 



A disintegrin and metalloprotease


Absorption, distribution, metabolism, elimination


Protein kinase B


Angiotensin II receptor type I


Bradykinin receptor


Regulatory B-cell


Cancer-associated fibroblast


Cytotoxic CD8+ T-cell


Elastin-binding protein


Extracellular matrix


Epidermal growth factor


Epidermal growth factor receptor


Epithelial-to-mesenchymal transition


Extracellular signal-related kinase


Focal adhesion kinase


Fibroblast growth factor


G protein-coupled receptor




Hepatocyte growth factor


Hypoxia-inducible factor 1


Hypoxia-inducible factor 2




Insulin growth factor-1




Insulin receptor


Insulin receptor β


Janus kinase


Lysophosphatidic acid


Endotoxin lipopolysaccharide


Mitogen-activated protein kinase


Myeloid-derived suppressor cell


Major histocompatibility complex




Matrix metalloprotease


Matrix metalloprotease inhibitor


Messenger RNA


Mammalian target of rapamycin complex 1


Neuromedin B GPCR




Oseltamivir phosphate


Pancreatic ductal adenocarcinoma


Platelet-derived growth factor-1




Phosphoinositide 3-kinase


phosphorylating insulin receptor substrate-1


Protective protein cathepsin A


Arginine-glycine-aspartic acid


Reactive oxygen and nitrogen species


Receptor tyrosine kinase


Src family kinase


Signal transducer and activator of transcription


Tumour-associated macrophage


Tumour-associated neutrophil


Tumour growth factor β


CD4+ T helper 1


Tumour-infiltrating lymphocyte


Tyrosine kinase inhibitor


Toll-like receptor


Tumour microenvironment


Triple negative breast cancer


Tumour necrosis factor α


Regulatory T-cell


Urokinase-type plasminogen activator


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


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Authors and Affiliations

  1. 1.Department of Biomedical and Molecular SciencesQueen’s UniversityKingstonCanada

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