Activation of fibroblasts in cancer stroma

Abstract

Tumor microenvironment has emerged as an important target for cancer therapy. In particular, cancer-associated fibroblasts (CAF) seem to regulate many aspects of tumorigenesis. CAFs secrete a variety of soluble factors that act in a paracrine manner and thus affect not only cancer cells, but also other cell types present in the tumor stroma. Acting on cancer cells, CAFs promote tumor growth and invasion. They also enhance angiogenesis by secreting factors that activate endothelial cells and pericytes. Tumor immunity is mediated via cytokines secreted by immune cells and CAFs. Both immune cells and CAFs can exert tumor-suppressing and -promoting effects. CAFs, and the factors they produce, are attractive targets for cancer therapy, and they have proven to be useful as prognostic markers. In this review we focus mainly on carcinomas and discuss the recent findings regarding the role of activated fibroblasts in driving tumor progression.

Introduction

Tumorigenesis is a multistep process, analogous to Darwinian evolution, whereby genetic changes lead to growth advantage in a subset of cells paving way to progression from normal to malignant cells [1]. Hanahan and Weinberg proposed the six hallmarks of cancer, that most, if not all tumors require for progression from benign to malignant growth. These hallmarks are: self-sufficiency in growth signals, insensitivity to antigrowth signals, capability to evade apoptosis, unlimited replicative potential, sustained angiogenesis and tissue invasion together with metastasis [2]. Recently, a seventh hallmark, cancer-related inflammation (CRI) was proposed by Colotta et al. [3]. CRI refers to induction of genetic instability by inflammatory mediators, leading to accumulation of genetic alterations. CRI is accompanied by tissue remodeling and angiogenesis [4], [5].

The majority of human cancers are carcinomas. They arise from the epithelial cell layer that under normal conditions is separated by basal lamina from the supporting connective tissue known as stroma [6]. Carcinoma was long viewed as a disease of transformed epithelial cells, and treatment strategies focused only on tumor cells. However, tumor progression is not achieved solely by the evolving cancer cells, but stromal components – the microenvironment of the tumor – play a key role in this process [7]. Co-evolution of tumor and stromal cells can occur in two ways: stromal changes may take place first leading to transformation of epithelial cells, or transformed epithelia may activate stromal cells in a paracrine fashion [8]. Various cell types are present in the tumor stroma. Vasculature, consisting endothelial and smooth muscle cells and pericytes, provides nutrients and oxygen [9]. Inflammatory and immune cells, recruited by chemokines and cytokines, have both tumor-suppressing and -promoting functions [10]. Quiescent fibroblasts become activated in tumor stroma and are key regulators of the paracrine signaling between stromal and cancer cells [11].