23 Invited lecture: Tumor–stroma interactions promote operational flexibility in cancer progression

Abstract

Malignant cancer cells do not act as lone wolves to achieve metastasis, as they exist within a complex ecosystem consisting of an extracellular matrix scaffold populated by carcinoma-associated fibroblasts (CAFs), endothelial cells and immune cells (De Wever and Mareel, J Pathol, 2003; De Wever et al., Int J Cancer, 2008; De Wever et al., Semin Cancer Biol., 2014). Paracrine interactions between CAFs, also termed myofibroblasts, and cancer cells stimulate invasion of colon cancer cells in matrix scaffolds. The pro-invasive activity was found also with the secretome and we identified the combined action of Scatter Factor/Hepatocyte Growth Factor (SF/HGF) and tenascin-C (TNC) to promote invasion (De Wever et al., FASEBJ, 2004). Secretome proteomics revealed the presence of multiple other pro-metastatic proteins suggesting that the molecular characteristics of a CAF remain in evolution (De Boeck et al., Proteomics, 2013). CAFs show operational flexibility; eg their ability to respond dynamically to a cancer cell’s fluctuating demands by shifting profitable signals necessary in metastasis. Local, tissue-resident fibroblasts and mesenchymal stem cells (MSCs) coming from reservoir sites such as bone marrow (BM) are the main progenitor cells of CAFs (De Boeck et al., Oral Oncol, 2010). A successful invader must survive in an ectopic environment and CAFs provide advantageous signals to cancer cells to accomplish survival through AKT activation. Neuregulin (NRG)-1 secreted by CAFs increase cancer cell number through HER2/HER3-dependent activation of the PI3K/AKT pathway. Translational data demonstrate transmembrane NRG-1 expression in CAF in primary colorectal cancer and in liver metastasis, with the strongest expression in the immediate vicinity of HER2/HER3 expressing cancer cells. Moreover, high transmembrane NRG-1 expression is a poor prognosis marker in colorectal cancer (De Boeck et al., GUT, 2013). The odds that an aggressive cancer cell will form a metastatic colony in some organ are vanishingly small. Nevertheless, metastasis is responsible for more than 90% of cancer-associated mortality; thus the clinical need to prevent or target metastasis is high. Viewing cancer within the context of ecosystems may provide opportunities to exploit CAFs to create tumor-environment bio-mimetics to deceive and redirect metastatic cancer cells.