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Targeting the Tumor Microenvironment to Overcome Resistance to Therapy

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

Abstract

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.

Keywords

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

Abbreviations

ADAM

A disintegrin and metalloprotease

ADME

Absorption, distribution, metabolism, elimination

AKT

Protein kinase B

AT2R

Angiotensin II receptor type I

BR2

Bradykinin receptor

Breg

Regulatory B-cell

CAF

Cancer-associated fibroblast

CTL

Cytotoxic CD8+ T-cell

EBP

Elastin-binding protein

ECM

Extracellular matrix

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transition

ERK

Extracellular signal-related kinase

FAK

Focal adhesion kinase

FGF

Fibroblast growth factor

GPCR

G protein-coupled receptor

HA

Hyaluronan

HGF

Hepatocyte growth factor

HIF-1

Hypoxia-inducible factor 1

HIF-2

Hypoxia-inducible factor 2

IFN-γ

Interferon-γ

IGF-1

Insulin growth factor-1

IL

Interleukin

IR

Insulin receptor

IRβ

Insulin receptor β

JAK

Janus kinase

LPA

Lysophosphatidic acid

LPS

Endotoxin lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MDSC

Myeloid-derived suppressor cell

MHC

Major histocompatibility complex

miRNA

MicroRNA

MMP

Matrix metalloprotease

MMPi

Matrix metalloprotease inhibitor

mRNA

Messenger RNA

mTORC1

Mammalian target of rapamycin complex 1

NMBR

Neuromedin B GPCR

NRP

Neuropilin

OP

Oseltamivir phosphate

PDAC

Pancreatic ductal adenocarcinoma

PDGF-1

Platelet-derived growth factor-1

PG

Proteoglycan

PI3K

Phosphoinositide 3-kinase

pIRS1

phosphorylating insulin receptor substrate-1

PPCA

Protective protein cathepsin A

RGD

Arginine-glycine-aspartic acid

RONS

Reactive oxygen and nitrogen species

RTK

Receptor tyrosine kinase

SRK

Src family kinase

STAT

Signal transducer and activator of transcription

TAM

Tumour-associated macrophage

TAN

Tumour-associated neutrophil

TGF-β

Tumour growth factor β

TH1

CD4+ T helper 1

TIL

Tumour-infiltrating lymphocyte

TKI

Tyrosine kinase inhibitor

TLR

Toll-like receptor

TME

Tumour microenvironment

TNBC

Triple negative breast cancer

TNF-α

Tumour necrosis factor α

Treg

Regulatory T-cell

uPA

Urokinase-type plasminogen activator

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

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

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