The presence of an inflammatory infiltrate is associated wit

The presence of an inflammatory infiltrate is associated with poor prognosis in a number of malignancies, including those with a predilection for metastasis to bone. CAFs are capable of promoting, and maintaining an inflammatory environment by recruiting immune cells; in particular monocyte/macrophage through secretions of cytokines and chemokines. Recruited macrophages are known to polarise towards mostly the tumour promoting M2 type which encourage angiogenesis, immune suppression and metastasis. Evidence demonstrates that CAFs recruit monocytes mostly through CCL2-CCR2 in breast cancer and melanoma, and CD68+ macrophages through CXCL14 in prostate cancer [8]. IL-6 secreted by CAFs encourages differentiation of CD14+CD1a− monocytes to macrophages . CAFs also recruit mast hydroxylase inhibitor through secreting IL-6, and T lymphocytes via CXCL9, CXCL10, and CXCL12 which promote angiogenesis and modulate immune responses to tumour cells . One of the major roles of normal fibroblast is to secrete components of extracellular matrix (ECM) and this property is retained in CAFs, however the ECM secreted is altered to support tumour growth and invasion. Many tumours are surrounded by a desmoplastic stroma; that is, one rich in collagen, fibronectin, and other ECM components, which has been associated with poor prognosis [9]. Early breast tumours show ECM stiffening due to cross linking of collagen catalysed by lysyl oxidase (LOX) expressed by CAFs, and stiffer ECM is known to promote aggressive growth in hypoxic cancer cells [9]. CAFs have an enhanced expression of fibronectin which has demonstrated a role in cell adhesion and increased metastatic potential in Lewis lung cancer, ovarian cancer, and melanoma [10]. Their role in maintaining ECM homeostasis makes fibroblasts an important component of mechanisms regulating tissue mechanics. Changes in ECM stiffness are frequently observed in the tumour microenvironment and are known to influence tumour cell and fibroblast phenotype (reviewed in Bonnans et al. [11]). Wong and colleagues demonstrated activation of focal adhesion kinase (FAK) in fibroblasts by mechanical forces leading to secretion of CCL2, consequently recruiting macrophages [12]. Evidence also exists supporting knockdown of FAK in CAFs in oral squamous cell carcinoma inhibited metastasis by minimizing CCL2 secretion [13]. The immune cells recruited as a result secrete cytokines and MMPs and may further modulate the ECM to promote metastasis. CAF in primary tumours also secrete a variety of factors that can directly influence the behavior of cancer cells and encourage distant metastasis. For example, stromal derived factor 1 (SDF-1/CXCL12), which interacts with cancer cells through CXCR4 inducing tumour growth and metastasis (including to bone) [14]. Other factors released by CAF, such as epidermal growth factor receptor (EGFR) ligands also promote tumour growth and metastasis by interacting directly with cancer cells [15]. Extracellular vesicles (EV, frequently erroneously referred to generically as exosomes) are also reported to play a role in the paracrine signaling between CAF and cancer cells [16], possibly through the delivery of microRNA which influence specific gene expression profiles in recipient cells [17].
The malignant stroma – conspirator in bone metastasis? Bone metastasis is a common and often devastating feature of several cancers; some subtypes of breast cancer and prostate cancer in particular show a predilection for dissemination to bone [18]. Once present in the bone microenvironment, malignant cells can stimulate bone destruction or formation leading to pain, fracture, hypercalcaemia, and spinal cord compression. The determinants of bone-tropic metastatic dissemination are poorly understood, but it is becoming evident that the primary tumour microenvironment may play a key role. CAF in particular are known to secrete elevated levels of several cytokines and growth factors found in the bone marrow microenvironment, suggesting that the primary stroma may be able to select for cancer cells able to thrive in bone. This hypothesis was given credence by the work of Zhang et al., who provided evidence that CAF in the primary tumour microenvironment of an aggressive and bone-tropic subclass of triple negative (TN; negative for estrogen receptor, progesterone receptor and HER2 amplification) breast cancers secrete factors such as IGF-1 and CXCL12 [19]. These cytokines select for cancer cells with high src activity and PI3K-Akt signaling which subsequently thrive in the bone microenvironment (illustrated in Fig. 2). In prostate cancer, TGFβ–dependent signals such as CXCL1 and CXCL16 derived from stromal CAF have been shown to promote growth of metastatic lesions in bone [20].