Primary tumor and metastasis-sectioning the different steps of the metastatic cascade.

Patients with lung cancer in the majority die of metastases. Treatment options include surgery, chemo- and radiotherapy, targeted therapy by tyrosine kinase inhibitors (TKIs), and immuno-oncologic treatment. Despite the success with these treatment options, cure of lung cancer is achieved in only a very small proportion of patients. In most patients' recurrence and metastasis will occur, and finally kill the patient. Metastasis is a multistep procedure. It requires a change in adhesion of tumor cells for detachment from their neighboring cells. The next step is migration either as single cells [epithelial-mesenchymal transition (EMT)], or as cell clusters (hybrid-EMT or bulk migration). A combination of genetic changes is required to facilitate migration. Then tumor cells have to orient themselves along matrix proteins, detect oxygen concentrations, prevent attacks by immune cells, and induce a tumor-friendly switch of stroma cells (macrophages, myofibroblasts, etc.). Having entered the blood stream tumor cells need to adapt to shear stress, avoid being trapped by coagulation, but also use coagulation in small veins for adherence to endothelia, and express homing molecules for extravasation. Within a metastatic site, tumor cells need a well-prepared niche to establish a metastatic focus. Tumor cells again have to establish a vascular net for maintaining nutrition and oxygen supply, communicate with stroma cells, grow out and set further metastases. In this review the different steps will be discussed with a focus on pulmonary carcinomas. The vast amount of research manuscripts published so far are not easy to analyze: in most reports' single steps of the metastatic cascade are interpreted as evidence for the whole process; for example, migration is interpreted as evidence for metastasis. In lung cancer most often latency periods are shorter, in between 1-5 years. In other cases, despite widespread migration occurs, tumor cells die within the circulation and do not reach a metastatic site. Therefore, migration is a requisite, but does not necessarily predict metastasis. The intention of this review is to point to these different aspects and hopefully provoke research directed into a more functional analysis of the metastatic process.