The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome

Abstract

The tumour microenvironment (TME) determines vital aspects of tumour development, such as tumour growth, metastases and response to therapy. Cancer-associated fibroblasts (CAFs) are abundant and extremely influential in this process and interact with cellular and matrix TME constituents such as endothelial and immune cells and collagens, fibronectin and elastin, respectively. However, CAFs are also the recipients of signals—both chemical and physical—that are generated by the TME, and their phenotype effectively evolves alongside the tumour mass during tumour progression. Amid a rising clinical interest in CAFs as a crucial force for disease progression, this review aims to contextualise the CAF phenotype using the chronological framework of the CAF life cycle within the evolving tumour stroma, ranging from quiescent fibroblasts to highly proliferative and secretory CAFs. The emergence, properties and clinical implications of CAF activation are discussed, as well as research strategies used to characterise CAFs and current clinical efforts to alter CAF function as a therapeutic strategy.

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…In case of acute inflammation, they are activated as myofibroblasts which are then recruited from the bone marrow to the injured tissue site and take over several processes that are important for wound healing. In response to chronic inflammation or tumor development quiescent tissue sessile fibroblasts are activated, which over time lead to a further disorganization of tissue architecture [ 84 ]. As CAFs can disseminate throughout the organism like tumor cells it is suggested that they play an additional role in metastasis [ 85 ].…”

Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance

“…With recent discoveries, it is increasingly appreciated that malignant tumor cells interact with their TME in a complex and reciprocal manner to regulate tumor progression and treatment response [ 1 , 2 , 3 , 4 , 5 ]. In addition to the ability of the individual stromal components to directly control tumor cell phenotype, interactions among the components of the TME themselves can also exert the same effects [ 6 , 66 ].…”

“…At every step of the tumor lifecycle, there is reciprocal communication between these malignant cancer cells and their neighbors. Their highly dynamic interactions control tumor initiation, progression, invasion, metastasis, and treatment resistance, which complicates cancer therapeutic planning [ 1 , 2 , 3 , 4 , 5 , 6 , 8 , 10 , 11 , 12 , 13 , 185 ]. Here, we reviewed how the tumor stroma can contribute to cancer radioresistance; many of which are mediated through secreted factors, cell surface receptors, and downstream pro-survival and/or anti-apoptotic signaling pathways.…”

“…The field of oncology has evolved from a malignant mutated cancer cell-centered view to the understanding of cancer as a complex “organ” composed of both malignant cells and diverse nonmalignant cellular and non-cellular components termed the tumor stroma or tumor microenvironment (TME) [ 1 , 2 , 3 , 4 , 5 ]. The concept of cancer as a disease focusing only on malignant tumor cells has been deemed inaccurate; in some cancers, stromal cells represent the majority of cell types, as is frequently seen in pancreatic and breast cancers [ 6 ].…”

“…The concept of cancer as a disease focusing only on malignant tumor cells has been deemed inaccurate; in some cancers, stromal cells represent the majority of cell types, as is frequently seen in pancreatic and breast cancers [ 6 ]. These cellular stromal components often include activated cancer-associated fibroblasts (CAFs), leukocytes, and vascular cells, but they also sometimes include other adjacent normal tissue/cells such as non-transformed epithelia, adipose tissue, or neurons [ 1 , 2 , 3 , 4 , 5 ]. The non-cellular compartment of the tumor stroma comprises extracellular matrix (ECM) components like collagens, laminins, fibrinogen, elastin, and proteoglycan, and secreted factors such as cytokines, chemokines, and sequestered growth factors [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”