Review Article
Triggering the landslide: The tumor-promotional effects of myofibroblasts

https://doi.org/10.1016/j.yexcr.2013.03.015Get rights and content

Abstract

Cancers become significantly more dangerous when the tumor progresses from in situ, or contained, to an invasive state, in which the cancer cells acquire the ability to pass through the surrounding basement membrane (BM), a specialized extracellular matrix (ECM) that provides structure and contextual information to the underlying tissue. While the majority of tumors are carcinomas, derived from epithelial cells, it is the stromal cells surrounding the epithelial-derived tumor cells, including fibroblasts and myofibroblasts, vasculature, and immune cells, that are largely responsible for the production and remodeling of the ECM. Here, we will discuss myofibroblasts as key effectors of tumor progression, focusing on recent advances in breast and pancreatic carcinoma, showing how myofibroblasts may function properly in normal tissue remodeling and wound-healing processes, how in the tumor context they can drive cancer invasion and metastasis, and how the pathogenic functions of myofibroblasts may be targeted therapeutically.

Introduction

Understanding the key factors in development and progression of a particular cancer type is critical for identifying therapeutic interventions that target cancer at the earliest stages of development. Environmental, nutritional, and hereditary factors that have been identified as associated with increased cancer risk could potentially reveal those processes essential for cancer development. Surprisingly, while cancer risk prediction models that incorporate such risk factors have been found to perform well at the population level, they have not translated to individualized cancer risk assessment [1]. Such findings have led to the realization that apart from the cancer cells, the composition and structure of the ECM plays an important inhibitory role in cancer development [2]. During a person's lifetime, individual cells may accumulate potentially tumorigenic genetic mutations, but only rarely do these develop into cancer. Cancer development might be viewed as a landslide, where somatic mutations can be viewed as pre-existing stresses, and exposure to carcinogenic toxins as a continuous rain. These mutations may lead to development of abnormalities, and even to carcinoma in situ, but so long as the underlying ECM remains intact, tumor development is slowed. Once myofibroblasts become activated, however, the ECM becomes damaged and degraded; the former solid surface becomes loose, leading to system collapses, systemic disease, and death.

The immune system can detect the existence of some oncogenic alterations, in a similar fashion to identification of viruses and bacteria. Initially, the immune system might attempt to “heal” the cancer in the same way it heals wounds, invading the tissue and transforming the phenotypes of resident cells [3]. What works well in wounds, however, can go awry in the innate fight against cancer, where the roles of myofibroblasts and even their origins are not entirely parallel. One major difference between wound myofibroblasts and tumor associated myofibroblasts is the ability of the latter to influence epithelial cells to proliferate and to drive malignant transformation [4]. Another difference is that in wounds, myofibroblasts appear to be differentiated from mesenchymal cells, while in the tumor microenvironment, myofibroblasts can develop directly from the epithelial cells as well as from the mesenchymal cells [5], [6].

In normal wound healing, the initiating damage causes the activation of the coagulation cascade that in turn activates the innate immune response. With the arrival of myeloid-derived immune cells, the signal for cytokine production leads toward activation of the adaptive immune system. Secreted cytokines activate fibroblasts and endothelial cells, which transform into myofibroblasts that stimulate angiogenesis, increase ECM production, and physically contract the wound edges, facilitating the healing process. The initiating factors including key cytokine Transforming Growth Factor-β (TGF-β) are eventually depleted as the wound heals, at which time the myofibroblasts disappear through apoptosis [3], [5]. If myofibroblasts persist, they transform the site into a chronic wound; examples of this phenomenon include skin keloids [7] and fibrosis of organs such as liver, lung or pancreas [8].

In cancer development, myofibroblasts are present in the stroma of most epithelial tumor types [9], [10], where they can act as drivers of malignant transformation. The tumor-associated myofibroblasts express matrix metalloproteinases (MMPs) which can degrade nearly every component of the ECM, including the BM; myofibroblasts also possess the ability to contract the ECM, which disrupts normal epithelial tissue structures and provides pathways for tumor cells to invade [11]. Secreted MMPs interact directly with the carcinoma cells, breaking down cell–cell junctions and adhesions, further facilitating tumor cell movement [12]. MMPs can also directly stimulate tumor progression through promotion of the epithelial–mesenchymal transition (EMT) [13], a developmental process that activates a migratory and invasive cellular phenotype in epithelial tumor cells and that can under chronic activation conditions cause epithelial cells to transition entirely into a myofibroblast phenotype [14].

Section snippets

Fibrosis and myofibroblasts

Myofibroblasts are ubiquitously found in the human body, in the skin during wound healing [8], [15], the heart [16], [17] and the intestines [4]. They are detectable by week 21 during embryogenesis [4] while in adults, stellate cells in liver, pancreas, and lung possess myofibroblast charateristics. During activation, myofibroblasts develop actin stress fibers and express α-smooth muscle actin (αSMA) [3], [15], [18], [19]. In 1972 Gabbiani et al. described fibroblasts in their ability to become

Cancer and myofibroblasts

Cancer-associated myofibroblasts possess many of the features found in nonmalignant tissue. However, there is an important difference: in normal wound healing, elevated levels of TGF-β1 in the wound microenvironment has a powerful cytostatic effect on epithelial cells, but once the epithelial cells have acquired specific mutations, the cytostatic effect of TGF-β is lost [38], [39]. Additionally, the metaplastic characteristic of tumors allows for a wider range of cellular differentiation

Current challenges, and future directions

The near ubiquitous co-occurrence of fibrosis with cancer in the pancreas [63], liver [19], [64], and kidney [45], and the fact that chronic fibrosis is a predisposing factor for cancer development in these and other organ systems [5], [8], [45], [65] points to a central role of myofibroblasts in tumor development. The recent identification of additional direct interactions between tumor cells and myofibroblasts that potentiate tumor malignancy further highlights the importance of these cells.

Acknowledgments

We thank Evette Radisky for helpful conversations and editing. This work is supported by NCI Grants CA122086, 132789 and by the Mayo Clinic Breast SPORE CA116201.

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