Turning foes to friends: targeting cancer-associated fibroblasts

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Abstract

Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell-cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment.

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Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

Alexandre Calon, Elisa Espinet, Sergio Palomo-Ponce … (2012)

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC. Copyright © 2012 Elsevier Inc. All rights reserved.

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Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

Mara Sherman, Ruth T Yu, Dannielle D. Engle … (2014)

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK: Copyright © 2014 Elsevier Inc. All rights reserved.

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Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

Matthew Kraman, Paul J Bambrough, James Arnold … (2010)

The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.