Effects of radiation on the metastatic process

Abstract

Radiotherapy remains one of the corner stones in the treatment of various malignancies and often leads to an improvement in overall survival. Nonetheless, pre-clinical evidence indicates that radiation can entail pro-metastatic effects via multiple pathways. Via direct actions on cancer cells and indirect actions on the tumor microenvironment, radiation has the potential to enhance epithelial-to-mesenchymal transition, invasion, migration, angiogenesis and metastasis. However, the data remains ambiguous and clinical observations that unequivocally prove these findings are lacking. In this review we discuss the pre-clinical and clinical data on the local and systemic effect of irradiation on the metastatic process with an emphasis on the molecular pathways involved.

Keywords: Cancer; Invasion; Metastasis; Radiation; Radiotherapy.

Fig. 1

Molecular pathways regulating cellular activities implicated in radiation -enhanced invasion and metastasis. Modified after Zhai et al., (2006b), Chargari et al., (2013), He et al., (2015b) and Lee et al., (2017b), with data from: Ahmed et al., (2013b); Asuthkar et al., (2011); Bastos et al., (2014); Chang et al., ; Cheng et al., (2006b); Cho et al., (2016b); Cui et al., (2015b); de Marcondes (2017); Dong et al., (2015b); Eke & Cordes, (2015b); Fujita et al., (2014b); Fujita et al., (2015c); Gu et al., (2015b); He et al., (2015b); Ho et al., (2010b); Kang et al., (2013); Yan et al., (2013b); Kim et al., (2016); Kuo et al., (2015b); Liu et al., (2014b); Park et al., (2006b); Pichard et al., (2011b); Rajput et al., (2015b); Yuan et al., (2015b); Zhai et al., (2006b); Zhou et al., (2011b). Green, red and white boxes are secretory, transmembrane receptor and intracellular signaling molecules respectively. The glowing box is a mitochondrion; the double line is DNA. Abbreviations: Akt, protein kinase B; AP1, activator protein 1; BclxL, B-cell lymphoma-extra large; Bmi-1, B cell-specific Moloney murine leukemia virus integration site 1; β-CTN, beta-catenin; CRK, CT10 regulator of kinase; CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor type 4; Dlx-2, distal-less homeobox-2; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EphA4, ephrin A 4; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GAB1, GRB2-associated-binding protein; GADD45a, Growth Arrest and DNA Damage inducible Alpha; GCSF, granulocyte colony stimulating factor; GCSFR, granulocyte colony stimulating factor receptor; GIRDIN, Guanine nucleotide-binding protein α subunit -interacting vesicle-associated protein; Gli1, Glioma-associated oncogen; GRB2, Growth factor receptor-bound protein 2; GSK3β, glycogen synthase kinase 3 beta; HGF, hepatocyte growth factor; HIF-1, hypoxia-inducible factor-1; IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; IL-6, interleukin 6; ILK, integrin-linked kinase; JAK, Janus kinase; LAP-β1, latency-associated peptide of TGF-β; MEK, mitogen-activated kinase kinase; MET, tyrosine-protein kinase Met; MMP, matrix metalloproteinase; mTOR, mechanistic target of rapamycin; NF-κB, nuclear-factor kappa-light-chain-enhancer of activated B cell; Nrf2, Nuclear factor E2 related factor 2; NSB1, Nijmegen breakage syndrome 1; p53, Tumor protein p53; PAI-1, plasminogen activator inhibitor 1; PAK1, p21- activated kinase 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Rac, Ras-related C3 botulinum toxin substrate; RACK1, receptor for activated C kinase 1; RAF, Rapid Accelerated Fibrosarcoma; RAP, Ras-proximate; RAS, Rat sarcoma; RhoA, Ras homolog gene family member A; RNS, reactive nitrogen species; ROS, reactive oxygen species; Src, sarcoma family kinase; SMAD, small and mothers against decapentaplegic; Smo, Smoothened; SOS, Son of Sevenless; STAT, signal transducer and activator of transcription; TCF, T-cell factor; TGF-β, transforming growth factor beta; TKB-1, tank-binding kinase-1; TSP1, Trombospondin 1; TβRII, TGF-β type II receptor; Wnt, Wingless-related integration site; ZEP1, Zinc finger E-box-binding homeobo× 1

Fig. 2

Schematics of mutual communication between cancer cells, tumor associated host cells and ecosystems. a Schematic of communication between cancer cells and tumor-associated host cells with invasion-related radiation-sensitive molecules. Arrows indicate the communication between cancer cells and tumor-associated host cells, namely fibroblasts, macrophages, lymphocytes, adipocytes, osteoclasts and endothelial cells, and between tumor-associated host cells, for example fibroblasts to endothelial cells. White text boxes overlapping the arrows contain the molecules implicated in this communication and shown to be sensitive to alterations by radiation. This intercellular communication establishes the individual local ecosystems that participate at metastasis as shown in panel b Adapted from Mareel et al., (2009b), with data from: Vakaet (2004); Abdollahi (2005); Chargari et al., (2013); De Bacco et al., (2011b); Gu et al., (2015b); Hamalukic et al., (2011b); Hirschhaeuser et al., (2011); Kuonen et al., (2012a); Li et al., (2016b); Madani et al., (2008); Nubel (2004); Vilalta (2016); Lee et al., (2017c). b Schematic of the communication between ecosystems of primary tumor, distant metastasis, lymph node and bone marrow, associated with metastasis and sensitive to ionizing radiation. Arrows indicate the communication between ecosystems, namely the primary tumor, lymph node, distant metastasis and bone marrow. Participating at this communication are host cells (smaller green ovals), cancer cells (smaller pink ovals) and molecules (white text boxes), all implicated in radiation-enhanced metastasis. Adapted from: Madani et al., (2008); Ceelen et al., (2014) and Willaert et al., (2014) with data from: Kioi et al., (2010b); Kuonen et al., (2012c); Russell & Brown (2013b); Vilalta (2016). Abbreviations: CC, cancer cells; CCL, C-C motif chemokine ligand; CSF1, macrophage colony-stimulating factor 1; CTC, circulating tumor cells; CXCL, C-X-C motif chemokine ligand; DC, dendritic cells; DTC,disseminated tumor cells; EPC, endothelial precursor cells; FGF2, basic fibroblast growth factor; GMCSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; HSC, hematopoietic stem cells; IGF1, insulin-like growth factor 1; IL, interleukin; LC, lymphocytes; MCC, metastatic cancer cells; MMP, matrix metalloproteinase; MSC, mesenchymal stem cells; OPN, osteoprotogerin; PDGF, platelet-derived growth factor; PlGF, placental growth factor; RANKL, receptor activator of nuclear kappa-B ligand; SC, stem cells; S-Lewis A, sialyl-Lewis A antigen; SCF, stem cell factor; SDF1 (also called CXCL12), stromal- cell derived factor 1; sVCAM1, soluble vascular cell adhesion molecule 1; TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor