Putting tumours in context

Abstract

The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

“…Therefore, based on the important similarities between SPARC and periostin in terms of expression in the desmoplastic tumoral stroma and their common stimulatory effects on the invasion and survival of tumour cells, our results suggest that periostin could act in a similar manner as other matricellular proteins by facilitating the development and progression of pancreatic cancer. It is now generally accepted that tumour cells modify the composition of the adjacent stroma by secreting their own extracellular matrix proteins to create a permissive and supportive environment for their growth (Bissell and Radisky, 2001;Koninger et al, 2004). This hypothesis is supported by the observation that periostin transcription is upregulated in pulmonary smooth muscle cells exposed to hypoxic conditions (Li et al, 2004), in damaged myocardial tissues where migration and resistance of cells to apoptosis is essential (Lindner et al, 2005;Litvin et al, 2005) and in the area around developing teeth where intense cell traction and cell stress occur (Rios et al, 2005).…”

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer

“…[10][11][12][13] Our group was the first that recognized concurrent and independent genetic alterations (LOH) in the stromal and epithelial cells of mammary carcinoma and raised the intriguing possibility that the mammary stroma in breast cancer may represent a neoplastic rather than a reactive response to the carcinoma. 1 Since publication of our previous observation, several other groups have confirmed the occurrence of genetic abnormalities in the normal-appearing stromal cells close to the breast carcinomas.…”

Anoikis: an emerging hallmark in health and diseases

“…The role of ECM as anoikis suppressor is well established [1,49] and several integrins (α1β1, α2β1, α3β1, α5β1, α6β1, α6β4, αvβ3) have a profound impact on cell survival [2,44,50] in both normal or neoplastic cells [2,51,52]. Key players in integrin-mediated signal transduction leading to anoikis protection are FAK, integrin-linked kinase (ILK), Src tyrosine kinase, PI3K, ERK and the adaptor protein Shc (Figure 2).…”