Seminars in Cancer Biology 20 (2010) 128–138 Contents lists available at ScienceDirect Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer Review Tumour-microenvironmental interactions: paths to progression and targets for treatment Carol Box, Susanne J. Rogers, Marta Mendiola 1 , Suzanne A. Eccles ∗ Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cotswold Rd, Belmont, Sutton, Surrey SM2 5NG, United Kingdom article info Keywords: Drug resistance Cancer progression Cell adhesion molecules Cell signalling Tumour microenvironment abstract Primary human tumours can often be eradicated by surgery if detected early; however metastatic disease renders complete cure less likely and the development of resistance to therapy results in tumour escape and increased risk of death. Interactions of tumour cells with each other, surrounding normal cells and extracellular matrix or basement membrane components are crucial to all stages of cancer progression. Changes in both cell–cell and cell–substrate proteins are linked to tumour cell migratory and invasive ability, induction of angiogenesis (on which sustained tumour growth and dissemination depends) and apoptosis resistance in response to drugs or radiotherapy. Hypoxia within solid tumours is a key driver of many aspects of progression, and may also nurture cancer stem-like cells which are increasingly linked to relapse and treatment failure. This review will briefly outline the cellular and molecular mechanisms underlying tumour progression, focussing on the acquisition of metastatic capacity and resistance to therapy. © 2010 Elsevier Ltd. All rights reserved. 1. Tumour-microenvironmental influences: the third dimension Most normal epithelial cells require continuous signals from their environment to survive (mediated via adhesive interactions with other cells or extracellular matrix (ECM) proteins) and loss of contact induces a specialised form of apoptosis, anoikis. Cancer cells, particularly those that have progressed to become metastatic, have generally overridden this requirement and three-dimensional (3-D) growth is associated with resistance to many forms of therapy [1]. It is surprising perhaps that standard testing of novel anti- cancer agents is still performed primarily in monolayer cultures [2,3]. However, there is a growing appreciation that 3-D assay systems may provide a more realistic and predictive drug test- ing environment [4–6]. Cell–matrix or (in the absence of matrix) cell–cell adhesion, mediated primarily by specific integrins [7] or cadherins [8], is frequently implicated in cell survival and chemoresistance in 3-D/spheroid cultures; a property known as “multicellular resistance” (MCR). Ivascu showed that breast cancer ∗ Corresponding author at: McElwain Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cotswold Rd, Belmont, Sutton, Surrey SM2 5NG, United Kingdom. Tel.: +44 20 8722 4210; fax: +44 20 8722 4134. E-mail address: Sue.Eccles@icr.ac.uk (S.A. Eccles). 1 Permanent address: Pathology and Oncology Lab, Research and Development Unit, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain. cells expressing epithelial (E)-cadherin or neuronal/mesenchymal (N)-cadherin spontaneously formed tight spheroids in suspen- sion culture whereas E-cadherin-negative cells formed only loose aggregates. The latter would form spheroids when cultured with Matrigel TM , but in this case the attachments were mediated by collagen I-1 integrin [3]. Others have shown that cells in 3-D cultures may upregulate expression not only of cadherins, but also of integrins to maintain the spheroid architecture; these levels more closely resemble those found in vivo [9]. Clearly such heterogeneous mechanisms could have different consequences for drug or antibody penetration [10], the signalling pathways that are activated, response to therapy and the strategies needed to overcome resistance in vivo [11,12]. Several studies have shown that “anti-adhesive” therapies (downregulation of E-cadherin or anti-integrin antibodies) can restore drug sensitivity in vitro. Zheng et al. showed that semaphorin 3F, a trans-membrane molecule that interacts with Neuropilin 2 to regulate nerve patterning and angiogenesis, is able to downregulate v3 integrin and restore drug sensitiv- ity in HT29 colon carcinoma 3-D spheroids [13]. In a similar study, Chen et al. achieved re-sensitisation of HT29 spheroids to 5-fluorouracil (5-FU) by silencing focal adhesion kinase (FAK), an integrin-associated kinase. Apoptosis was increased, apparently via the PI3K–AKT pathway. In tumours generated from cells in which FAK was knocked down, growth was inhibited and response to 5-FU was enhanced [14]. The FAK inhibitor PND-1186 selectively inhib- ited tumour cell growth in 3-D (but not 2-D) cultures. In vivo it induced apoptosis in a murine breast carcinoma model and inhib- 1044-579X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2010.06.004