Abstract
This review summarizes the roles of CAFs in forming a “cancerized” fibrotic stroma favorable to tumor initiation and dissemination, in particular highlighting the functions of the extracellular matrix component hyaluronan (HA) in these processes. The structural complexity of the tumor and its host microenvironment is now well appreciated to be an important contributing factor to malignant progression and resistance-to-therapy. There are multiple components of this complexity, which include an extensive remodeling of the extracellular matrix (ECM) and associated biomechanical changes in tumor stroma. Tumor stroma is often fibrotic and rich in fibrillar type I collagen and hyaluronan (HA). Cancer-associated fibroblasts (CAFs) are a major source of this fibrotic ECM. CAFs organize collagen fibrils and these biomechanical alterations provide highways for invading carcinoma cells either under the guidance of CAFs or following their epithelial to mesenchymal transition (EMT). The increased HA metabolism of a tumor microenvironment instructs carcinoma initiation and dissemination by performing multiple functions. The key effects of HA reviewed here are its role in activating CAFs in pre-malignant and malignant stroma, and facilitating invasion by promoting motility of both CAFs and tumor cells, thus facilitating their invasion. Circulating CAFs (cCAFs) also form heterotypic clusters with circulating tumor cells (CTC), which are considered to be pre-cursors of metastatic colonies. cCAFs are likely required for extravasation of tumors cells and to form a metastatic niche suitable for new tumor colony growth. Therapeutic interventions designed to target both HA and CAFs in order to limit tumor spread and increase response to current therapies are discussed.
Highlights
Cancers have been studied as diseases whose initiation and progression are caused by the mutation of key oncogenic “driver” genes, loss of suppressor genes and increasing mutational load resulting in genomic instability, immortalization, unrestrained growth and acquisition of colonizing potential (Hanahan and Weinberg, 2011; Garraway and Lander, 2013; Tomasetti et al, 2013; Vogelstein et al, 2013)
Tumor cells can be reverted into a normal growth state while retaining a highly mutated genome by blocking signaling pathways commonly activated by tumor microenvironment (Illmensee and Mintz, 1976; Hall et al, 1995; Wang et al, 2002; Kenny and Bissell, 2003; Postovit et al, 2008; Bizzarri et al, 2011; Northey et al, 2017)
We focus upon the roles of carcinoma-associated fibroblasts (CAFs), known as tumor-associated fibroblasts (TAFs), in creating a remodeling extracellular matrix that drives tumor initiation and mediates tumor cell spread
Summary
Cancers have been studied as diseases whose initiation and progression are caused by the mutation of key oncogenic “driver” genes, loss of suppressor genes and increasing mutational load resulting in genomic instability, immortalization, unrestrained growth and acquisition of colonizing potential (Hanahan and Weinberg, 2011; Garraway and Lander, 2013; Tomasetti et al, 2013; Vogelstein et al, 2013). Chick embryos injected with an oncogenic virus only developed tumors at wound sites even though the viral genome was expressed in unwounded tissues (Dolberg et al, 1985) These original results predicted that while oncogenic insults (e.g., mutations, oncogenic viruses) are a first step toward initiation of cancer, the status of host microenvironment is critical and rate-limiting for disease initiation and progression. Expression differences in normal vs cancer stroma have been mined to identify signatures that add independent prognostic information to classical epithelial biomarkers (Berdiel-Acer et al, 2014; Bedognetti et al, 2015; Nannini et al, 2015; Winslow et al, 2015; Colangelo et al, 2017; Petitprez et al, 2017) These unbiased analyses together with experimental evidence predict the critical importance of neovascularization, inflammation, immune tolerance and fibroblast activation in creating a “cancerized” microenvironment. We conclude by reviewing current experimental interventions targeting both stroma ECM and/or CAF functions that may limit tumor spread and improve current therapies
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