The tumour microenvironment: a novel target for cancer therapy

Abstract

Cancer therapy is in the midst of a major paradigm shift. Traditionally, cancer treatments have focused on tumour cells. However, studies over the past few decades have demonstrated that cancer is a vastly complex entity with multiple components affecting a tumour’s growth, invasion and metastasis. These components, collectively termed the ‘tumour microenvironment’, include endothelial cells, pericytes, fibroblasts, inflammatory cells, leucocytes and elements of the extracellular matrix (ECM). Biological agents that target components of the tumour microenvironment may provide an interesting alternative to traditional tumour cell‐directed therapy. Because of the complexity of the tumour milieu, the most beneficial therapy will likely involve the combination of one or more agents directed at this new target. This review highlights recent preclinical and clinical studies involving agents that target tumour vasculature, leucocytes, pericytes, cancer‐associated fibroblasts and ECM components. We pay particular attention to combination therapies targeting multiple components of the tumour microenvironment, and aim to demonstrate that this strategy holds promise for the future of cancer treatment.

Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor

“…Examples include avb3 and avb5 inhibitor cilengitide, which is currently being tested on glioblastoma patients in a phase III trial (Desgrosellier & Cheresh 2010). An excellent summary of recently developed novel agents targeting the tumour microenvironment can be found elsewhere (Hanna et al 2009). ECM structural defects seem more difficult to treat, although the regenerative capacity of stem cells are being explored in different tissues; the problem encountered in recent attempts is that the injured microenvironment loses conformity with fibrotic scarring, thus resulting in a noninducing environment where the stem cells cannot remodel (Berry et al 2006).…”

The tumour and its microenvironment – a complicated interplay

“…Growing tumour tissue is a complex system incorporating a multitude of relationships and loops between its various elements [1,2]. Any attempt to explore tumour biology only by investigating the properties of tumour cells is an incomplete and inadequate approach which disregards the significant influence of non-cancerous elements of the tumour's immediate environment on its growth and progression.…”

“…All the elements are actively involved in tumour growth and progression and may either promote or inhibit the processes enumerated above [1,2].…”

“…The growth of new blood vessels, a process called angiogenesis, is induced by the tumour's pro-angiogenic factors including VEGF, angiopoietin 1 and 2 [12,13], as well as several other important factors: FGF-β (fibroblast growth factor β), TGF-β and IL-8 [14]. In normal physiological conditions the above factors trigger angiogenesis at wound sites and in regenerative processes [1]. New vessel creation also occurs during embryogenesis [15].…”

A novel angiogenesis model for screening anti-angiogenic compounds: The chorioallantoic membrane/feather bud assay

“…Furthermore, angiogenesis and vasculogenesis, the development of new blood vessels, play an important role in the induction and maintenance of a variety of pathological states. Some of these manifestations are characterized by neovascularization, including diabetic retinopathy, glaucoma, age-related macular degeneration and cancer (2)(3)(4). Angiogenesis is essential for the growth and metastasis of malignant tumors.…”