Stromal fibroblasts in cancer initiation and progression

Abstract

PrefaceIt is widely accepted that the development of carcinomas, the most common type of human cancer, is due to accumulation of somatic mutations in epithelial cells. The behavior of carcinomas is also influenced by the tumour microenvironment that includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than previously appreciated. These new findings also have therapeutic implications.Work over the past two decades have delineated the genetic lesions that occur in epithelial cells leading to the initiation and progression of carcinomas, the most common form of human cancer 1 . The discoveries of genetic changes in somatic cancer cells have not only advanced our basic understanding of tumour formation but also significantly influenced the treatment of cancer with the use of new therapies targeted to specific pathways affected by genetic lesions (see Overview).Carcinoma cells, like normal epithelial cells, live in a complex microenvironment that includes the extracellular matrix (ECM), diffusible growth factors and cytokines, and a variety of non-epithelial cell types, including those comprising the vasculature (endothelial cells, pericytes, smooth muscle cells), those that can respond to infection and injury (lymphocytes, macrophages, mast cells), and fibroblasts. It has long been recognized that carcinomas induce a modified stroma through expression of growth factors that promotes angiogenesis, altered ECM expression, accelerated fibroblast proliferation, and increased inflammatory cell recruitment 2, 3 (Figure 1).Blood vessels are a critical component of the tumour microenvironment. Without formation of new blood vessels, carcinomas cannot grow beyond a very small size or metastasize and reform in distant organs 4 . Tumour angiogenesis is due in part to secretion of endothelial growth factors by tumours, and indeed, a targeted therapy (Avastin) that blocks the action of one of these factors (VEGF) has recently been approved (see also Overview) 5 .There is also a functional relationship between inflammation and cancer9. Cancers frequently arise in areas of chronic inflammation [see also review article by Beachy]. Examples include colon carcinoma associated with inflammatory bowel disease, stomach cancer in H. pylori infection, and hepatocellular carcinomas in hepatitis C infection. Inflammatory cells are also a key component of the microenvironment of carcinomas arising * To whom Correspondence should be addressed. 649 Preston Research Building, Nashville, TN 37232, hal.moses@vanderbilt.edu. NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 March 8. The three-dimensional structure supporting epithelia through the ECM is critically important, and impaired interactions of epithelial cells with ECM can result in transformation of the epithelia 6,7 . The specialized ECM that separates the epithelial and endothelial cells from the strom...

MET signalling: principles and functions in development, organ regeneration and cancer

“…In most tumours, MET is transcriptionally induced by hypoxia and inflammatory cytokines or pro-angiogenic factors that are abundant in the reactive stroma of full-blown tumours 34,136 . Hence, MET activation is a late event that aggravates the intrinsic malignant properties of already transformed cells by conveying proliferative, anti-apoptotic and promigratory signals (a biological situation that our group calls 'oncogene expedience') 23 .…”

“…Cells of mesenchymal origin are the major source of HGF, which acts in a paracrine manner on epithelial cells that express the MET receptor 32 . During tissue repair and cancer invasion, several cytokines that are abundant in the reactive interstitial compartment -for example, interleukin-1 and -6, tumour necrosis factor-α and transforming growth factor-β (TGFβ) -induce transcriptional upregulation of both HGF (in fibroblasts and resident macrophages) and MET (in epithelial cells) 33,34 . The inflammatory and tumour stroma also overexpress proteases that are involved in pro-HGF activation, such as the plasminogen activation system and matriptase 35,36 .…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…Accumulating evidence indicates that the tumor environment contains cells and cytokines that actively suppress primed effector T cells [74,75]. High concentrations of transforming growth factor-β (TGF-β), produced by cancer cells or stromal cells, are frequently found in solid tumors and interfere with effective immune rejection of tumor [76].…”

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…The CAFs were shown to mediate cancer‐related inflammation by expressing proinflammatory and tumor‐promoting factors and promotion of the cancer cell invasion and ECM remodeling 30, 31. Moreover, under the control of a variety of stroma‐modulating factors, the cancer cells themselves generate a permissive microenvironment favoring further tumor development and invasion 32, 33, 34…”