Jamil and Kasi highlighted the importance of tumor-derived exosomes containing proteins, DNA, RNA, and non-coding RNA. Tumor-derived exosomes may prepare the pre-metastatic niche, and establish a microenvironment at distant sites (Jamil and Kasi, 2021). Tumor-derived exosomes promote angiogenesis and EMT (Mashouri et al., 2019). TGF-β, IL-6, HIF1α, β-catenin, vimentin, casein kinase, and several EMT-inducer microRNAs (miRNAs) such as miR-301a-3p, miR-146a, miR-155, and miR-32-5p in tumor-derived exosomes are essential factors in the EMT mechanism (Mashouri et al., 2019). In the EMT mechanism, the miRNAs such as miR-200 family, miR-27a, miR-95-3p, miR-195, and miR-133 may be associated with lung metastasis. In colorectal cancer, the overexpression of miR-885-5p induced cell migration and invasion, which was associated with the development of liver and lung metastases (Jamil and Kasi, 2021). Tumor-associated macrophages, major components of tumor microenvironment associated with cancer metastasis, induce EMT for colorectal cancer migration and circulating tumor cell-mediated metastasis via JAK2/STAT3/miR-506-3p/FoxQ1 axis activated by IL-6 (Wei et al., 2019).

Systematic symptoms of patients with lung metastasis are fatigue, nausea, anorexia, and weight loss, while localized symptoms include pleurisy/pleural effusion, cough, dyspnea, hemoptysis, scalp metastasis, electrolyte disturbances, Pancoast tumor, and superior vena cava syndrome (Jamil and Kasi, 2021). Several evaluations for detecting lung metastasis may include a chest X-ray, computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), and flexibltracheobronchoscopy with endobronchial ultrasound (EBUS). Jamil and Kasi indicated that specific patterns associated with different tumors on chest imaging of CT include diffuse miliary seeding, large singular metastases, calcification of metastases, and cavitation of pulmonary metastases (Jamil and Kasi, 2021). Treatment options for lung metastasis include chemotherapy where drug resistance and toxicity are the main problems, immunotherapy such as cytokine therapy, and radiation. Surgery may be an option if metastases are restricted to the lungs. The criteria for selecting patients are technical resectability, tolerable general and functional surgical risk, control of the primary tumor process, and exclusion of any further extrathoracic metastasis. A long disease-free interval between the treatment of the primary tumor and the discovery of pulmonary metastases, absence of thoracic lymph nodes metastases, and a small number of pulmonary metastases are favorable prognostic factors (Jamil and Kasi, 2021). According to Jamil and Kasi, special considerations may be needed for specific cancers in terms of surgery. Indications for removal include all residual tumors after chemotherapy and normalization of tumor markers, recurrence after chemotherapy treatment, failure to respond to chemotherapy, and partial response to chemotherapy. In case surgery is no option for pulmonary metastasis, radio frequency ablation (RFA) may be a choice. In colorectal cancer, about 20% of the patients develop lung metastasis, where RFA in combination with systemic chemotherapy may improve the median survival duration. RFA can be also applied for renal cancer and hepatocellular carcinoma (Jamil and Kasi, 2021).

The prognosis of lung metastasis varies depending on the type of tumor, molecular biomarkers, extent of the disease, or treatment modalities (Jamil and Kasi, 2021). Complications include chemotherapy side effects as oral and gastrointestinal mucositis and chemotherapy-induced peripheral neuropathy, postsurgical complication as infection, atelectasis, cardiac arrhythmia, stroke, myocardial infarction, prolonged air leak and renal failure, and radiation side effects as radiation pneumonitis and post-radiation tumors (Jamil and Kasi, 2021). Since there have emerged new potential therapeutic approaches including phospholipase A2 inhibitors, long non-coding RNAs as therapeutic or diagnostic markers (Chen et al., 2016), bergamottin inhibiting EMT (Ko et al., 2018), and frondoside A (Attoub et al., 2013), further elucidations and investigations are needed for the treatment of lung metastasis.