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  • br Several mechanisms by which tumor cells metastasize to specific


    Several mechanisms by which tumor cells metastasize to specific organs have been proposed [15]. An important factor is the anatomy of the vascular and lymphatic drainage routes from the primary tumor sites (the anatomical-mechanical hypothesis) [15]. The liver is the organ at which a tumor from the gastrointestinal tract first arrives via the portal venous system. Muscle contractions may prevent metastatic cancer cell survival by inducing high tissue pressure and variable local blood flow [13]. Biomechanical destruction of cancer cells injected into the muscle was observed following electrical stimulation of the muscle [16]. Blood flow is highly variable when a muscle is in the con-tractile state, and it may destroy circulating cancer cells [13,17]. Another mechanism of metastasis to specific organs is the “seed and soil” hypothesis [13,18]. Some tumor cells (seeds) grow preferentially in the selected organs (soil) in which a suitable microenvironment is provided. In this re-gard, many factors including cytokines, growth factors, and other molecules are involved in a complex manner. Hepa-tocyte growth factor (HGF)/c-Met signaling has an important role not only in the maintenance of the homeostasis of the liver by hepatocytes but also in the progression of cancers, including lung cancer. HGF overexpression is a mechanism of acquisition of EGFR-TKI resistance [19]. HGF produced by fibroblasts enhances lung cancer progression [20]. Muscles provide a special microenvironment that includes elevated lactic Cyclophosphamide production, hypoxia, local pH instability, and reactive oxygen species generation, and this microenviron-ment differs from those in more frequent metastatic sites such as the bone and liver. This may result in unfavorable conditions for cancer cell survival and the subsequent development of detectable metastatic lesions [13,21].
    Another important finding of the present study is that muscle and skin metastases were associated with a lower response rate to first-line therapy. There are several possible explanations for the lower responsiveness among patients with these metastases. First, the tumor burden may be related to the therapeutic effect. A popular concept in cancer chemotherapy is that smaller tumors are more sensitive to chemotherapy than are larger tumors, as reported in animal studies [22, 23]. Confluence-dependent resistance to a chemotherapeutic agent also supports this “smaller is more sensitive” theory [24]. In addition, the neutrophil and lymphocyte counts can change during tumor progression, which alters the host immunological conditions with respect to tumor resistance and affects the efficacy of
    chemotherapy, EGFR-TKIs, and immune-checkpoint in-hibitors [25e29]. The elevated blood cell counts are prog-nostic factors [30]. Second, driver gene mutations were detected less frequently in our patients with metastases in the muscle (2 of 19 patients, 11%) or skin (1 of 13 patients, 8%) than in the total population (90 of 400 patients, 23%), even though this difference was not significant. Driver gene mutation-matched TKIs provided greater antitumor efficacy than did chemotherapy. Whether the lower frequency of driver gene mutations in patients with muscle or skin metastasis is accidental or a necessity should be clarified in future studies. Third, tumors that spread to some specific organs may have distinct tumor characteristics. Pleural dissemination and liver metastasis are associated with a decreased incidence of KRAS mutation [31]. Bone metastases are more frequent in central tumors than in peripheral tu-mors [32]. Differences in tumor characteristics and patients’ prognoses between central and peripheral tumors have also been reported [33,20]. Tumors that are able to use the muscle and skin as appropriate “soil” and develop at those sites may have an originally strong malignant potential.