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.

Figure 1. Normal versus malignant breast tumours

a. The normal mammary gland shows a highly structured and segregated architecture. Ducts are formed by a double layer of cells: luminal epithelial cells surrounded by a layer of myoepithelial cells, enclosed by the basement membrane. Stromal fibroblasts secrete a collagenous extracellular matrix (ECM), and blood vessels are centrally located and well defined. b. Lobular breast carcinoma is less organized. Tumour angiogenesis produces poorly defined blood vessels, and carcinoma cells intermingle with all the stromal elements.

Figure 2. Mechanisms of cell–cell and cell–ECM interactions

Integrin and non-integrin cell-surface receptors form attachments with the actin filaments in the cytoskeleton, and are able to sense elements of the extracellular matrix (ECM) to promote growth-factor activation. Tight junctions act as a barrier to the diffusion of solutes through the intercellular space and act as a boundary between the apical and basolateral plasma-membrane domains. Adherens junctions, which consist of extracellular E-cadherin dimers connected to cytoplasmic α- and β-catenin molecules, are anchored to actin filaments. Gap junctions provide a communication mechanism by allowing solutes and small signalling molecules to pass between adjacent cells. Desmosomes serve as anchoring points for INTERMEDIATE FILAMENTS and also provide signalling information.

Figure 3. Differences in stroma between tumours

Interstitial stromal cells of normal and breast tumour tissues differ in levels of smooth muscle differentiation. a. Normal interstital stroma(s) does not express smooth muscle actin (red) or b. smooth muscle myosin (green), indicating that smooth muscle differentiation has not taken place, although these cells do produce blood vessels (bv). c–f. Tumour tissues, by contrast, express high levels of smooth muscle actin (c,e). These images also show, however, that not all tumour stroma are similar. The tumour stroma shown in (c) and (d) expresses smooth muscle actin (c) but not smooth muscle myosin (d). In the tumour shown in e and f, the stromal cells express high levels of both actin and smooth muscle myosin. Adapted from REF. .

Figure 4. The tumour microenvironment assay

a. Primary breast carcinoma cells form spherical colonies when cultured in three-dimensional collagen type I. b. Co-cultivation with stromal cells, however, causes the tumour cells to spread and become invasive. The degree of tumour growth increases with the density of the stromal cells. Staining of the coculture assay (c) and of tumour (d) with anti-vimentin antibody reveals the structural similarities of stromal cells in the presence or absence of cancer cells. (Reproduced with permission from REF. © (1995) American Society for Clinical Investigation.)