Does ionizing radiation stimulate cancer invasion and metastasis?

Radiotherapy (RT) is a form of local treatment used mainly for malignant tumors. Such tumors originate from mutated stem cells. During their development they do attract a variety of host cells, coined tumor-associated host cells. Malignant tumors are characterized by uncontrolled growth, invasion and metastasis, the latter being the major cause of death of patients, even when their primary tumor is under control. RT inhibits growth. There are, however, clinical data suggesting that, under some circumstances, it may stimulate metastasis. DNA is a target of ionizing radiation (IR), though not the only one. IR produces cascades of growth factors and chemokines; it activates molecules initiating multiple signaling pathways that modulate several cellular functions. We consider cancer as a network of ecosystems, including at least the founder primary tumor, the site of metastasis and the bone marrow. As these ecosystems are in continuous communication, it is not surprising that RT of the primary tumor influences metastasis. Indeed, experiments with cells in culture and with animal tumors have shown that IR stimulates invasion and metastasis and activates pro-invasive and prometastatic cellular activities through upregulation of key molecules. At certain doses and within certain time frames, IR enhances the activities of the tumor-associated host cells that support invasion and metastasis, namely: endothelial cells building new vessels; leucocytes and macrophages causing inflammation; myofibroblasts initiating desmoplasia; osteoblasts and osteoclasts establishing bone metastasis; nerve cells producing efferent growth- and invasion-promoting molecules. Techniques such as spatially fractioned radiotherapy and hadron therapy may have different effects on metastasis. Taking into consideration the dose- and time-dependency of the IR-induced tumor-associated host cell reactions, these techniques, as well as the conventional ones, should be combined with repetitive biological imaging, reevaluation of planning and eventual replanning during the course of the treatment.