Clinical & Experimental Metastasis最新文献

Brain metastasis is a serious complication of non-small cell lung cancer (NSCLC) that contributes to poor survival outcomes despite strides made in systemic treatment regimens. The G protein-coupled receptor GPR183 has been shown to regulate immune cell positioning; however, its role in lung cancer metastasis remains unclear. In this study, the specific effects of G-protein coupled receptor 183 (GPR183) on lung cancer cell phenotypes and a mouse brain and lung metastasis model were investigated in vitro and in vivo. Lung cancer cell lines with GPR183 overexpression were assessed for proliferation, apoptosis, and cell cycle progression through CCK-8, flow cytometry, and immunoblotting. Wound healing, Transwell migration, and invasion assays were used to investigate the metastatic potential of GPR183-overexpressing cells. Subcutaneous xenograft and lung metastasis models were used to examine the growth and metastasis ability of GPR183-overexpressing cells. Moreover, a brain metastasis model was established using A549 cells that were injected into mice, and tumor burden was monitored using bioluminescence imaging and IHC staining. The overexpression of GPR183 inhibited lung cancer cell proliferation, migration, and invasion by inhibiting ERK and Akt pathways. GPR183 also reduced angiogenesis in co-cultured endothelial cells and limited the invasion of lung cancer cells through the blood-brain barrier. In the mouse model, GPR183 significantly reduced metastatic burden. These findings suggest that GPR183 inhibits NSCLC visceral metastasis by modulating angiogenesis and metastatic pathways, presenting a potential therapeutic target for preventing brain metastasis in lung cancer patients.

Introduction of immune checkpoint inhibitors (ICI) has improved overall survival (OS) for advanced non-small cell lung cancer (NSCLC). However, responses differ greatly amongst patients. Additional radiotherapy (RT) may promote tumor-specific immunity and synergize with ICI to improve tumor control. The multicenter phase II FORCE trial evaluated safety and efficacy of nivolumab with additional palliative radiotherapy (5 × 4 Gy) as clinically indicated in pre-treated metastatic non-squamous NSCLC (group A, n = 41), including pretreated patients without an indication for radiotherapy in a parallel cohort as real-world controls (group B, n = 60). With an objective response rate (ORR) of 8.3% in group A (n = 41), the primary endpoint was not met (p = 0.991). ORR in group B (n = 60) was 23.8%. Patient characteristics indicated a significantly poorer baseline clinical condition for group A compared to B, including worse Eastern Cooperative Oncology Group (ECOG) performance status (PS, p = 0.020) and more metastatic sites (p = 0.009). Consequently, group A had shorter progression-free survival (median PFS, 1.9 versus 3.7 months, hazard ratio [HR] 1.69 [95% CI (1.10, 2.58)]) and OS (median 6.0 versus 12.6 months, HR 1.75 [95% CI (1.07, 2.84)]). In multivariable analyses for the intention-to-treat (ITT) population, ORR, PFS and OS were inversely associated with the patients' ECOG PS (ORR odds ratio [OR] 0.126, p = 0.004) and correlated positively with tumor PD-L1 expression (ORR OR 12.8, p = 0.022), but not with radiotherapy administration (p = 0.169-0.854). Adverse events were distributed equally in both groups. Addition of palliative radiotherapy to nivolumab was safe and feasible, but not associated with improved efficacy. Patients with an indication for palliative radiotherapy have an inherently worse prognosis which cannot be overcome by radiation-induced immunostimulation. Clinical features and PD-L1 expression influence clinical outcomes more than radiotherapy administration and should be considered when evaluating the effectiveness of immuno-/radiotherapy combinations.ClinicalTrials.gov identifier: NCT03044626.

Triple-negative breast cancer is associated with poor patient prognosis and high rates of distant metastasis. These patients are at elevated risk of brain metastasis, which remains a major therapeutic challenge. IL13RA2, a high-affinity receptor for IL13, is highly expressed in primary brain cancers, many extracranial solid tumors, and in lung- and brain-seeking metastatic variant cell lines. However, the relationship between IL13RA2 and patient prognosis is variable, and the biological function of this receptor in cancer remains controversial. We sought to define the role of IL13RA2 in triple-negative breast cancer growth and metastasis, with an emphasis on breast-to-brain metastasis. We generated IL13RA2-CRISPR knockout derivatives of the human brain-seeking breast cancer cell line MDA231BrM2, as well as murine 4T1 cells, and evaluated changes in gene expression, proliferation, survival, and metastatic growth in vivo. Both IL13RA2-deficient models demonstrate enhanced cell survival in vitro, as well as augmented metastatic tumor growth and worsened animal survival in intracardiac models of brain metastasis. Concordantly, elevated IL13RA2 mRNA expression is positively correlated with overall survival in patients with basal-like breast cancer. Mechanistically, IL13RA2-deficient cells exhibit increased AKT and NF-κB signaling. These cells are sensitive to inhibition of either pathway, but especially AKT, which may represent a clinically useful vulnerability for patients with IL13RA2-low tumors. Our data suggest that inhibition of IL13RA2, though promising in other tumor contexts, may be deleterious in metastatic triple-negative breast cancer.

Histopathological growth pattern (HGP) is emerging as a promising pathological biomarker in liver metastases, with potential associations to prognosis and response to antiangiogenic therapy. Nonetheless, its prognostic role requires further elucidation for substantial heterogeneity of previous studies. We searched PubMed, Web of Science, Embase and Cochrane Library for studies comparing the overall survival (OS) or disease-free survival (DFS) between different HGPs in liver metastases from various cancer types. Data were pooled using hazard ratios (HRs) along with 95% confidence intervals (CIs) according to fixed or random-effects models. Subgroup analysis was also performed to adjust critical confounders. In total, 36 studies were included in the final analysis. It was demonstrated that desmoplastic HGP (dHGP) was associated with favorable OS compared with non-dHGP (HR, 0.59; 95% CI 0.54-0.64), replacement HGP (rHGP, HR, 0.60; 95% CI 0.49-0.74) and pushing HGP (pHGP, HR, 0.63; 95% CI 0.43-0.92), respectively. Similarly, dHGP also demonstrated improved DFS compared with non-dHGP (HR, 0.58; 95% CI 0.52-0.65), rHGP (HR, 0.61; 95% CI 0.49-0.77) and pHGP (HR, 0.51; 95% CI 0.31-0.83), respectively. In subgroup analysis, dHGPs remains an independent prognostic factor regardless of critical confounders, such as the preoperative systemic therapy, cancer types and HGP categorization criteria. This study confirmed the prognostic role of HGPs in liver metastases receiving surgical resection. Clinically, adding HGPs in prognostic models may provide further optimization.

The modern use of neoadjuvant and conversion systemic therapy in patients with colorectal cancer liver metastasis (CRLM) has improved resection rates and changed the borders between "resectable" and "unresectable" disease. Also, the use of preoperative systemic therapy has resulted in an increased frequency of disappearing liver metastasis (DLM). The optimal management of DLM is still controversial. In this review, we explore the current literature and highlight key findings relating to the tumor biology, diagnosis and treatment options of DLM. The definition of DLM should be based on hepatobiliary contrast MRI, which is the most sensitive preoperative imaging method. Patients with DLM are younger and more often have normalized their CEA-levels, and they have a better survival than those without DLM, likely reflecting favorable tumor biology and effective treatment response. Recent data indicate that molecular profiling (e.g. APC mutations) may predict CRLM at highest risk for vanishing after chemotherapy. However, just because the lesion has disappeared on imaging does not mean that there is a complete histopathological response. However a "watch and wait" strategy for patients with DLM is not associated with a reduced survival compared to resected DLM, but may be associated with a higher rate of recurrence often available for "rescue therapy", i.e. ablation or resection at the time when DLM recur and become visible. Furthermore, very few of "blind resections" of DLM contain viable tumor cells. International surveys among practicing hepatobiliary surgeons have revealed a widespread variation in the clinical management of DLM. In the future, biopsy and sequencing of metastases may be considered for therapeutic decision making in patients with CRLM considering the intricate tumor heterogeneity and clonal evolution of the disease.

Metastatic cancer has been considered uniformly fatal in the past with very poor outcomes for most cancer sites. However, novel systemic and targeted therapies have rendered unique responses with longer survival across several cancer types and metastatic sites. In addition, improved surgical experience and safety with good outcomes has made metastasectomy as an alternative curative-intent treatment across multiple organ sites. The pancreas is an uncommon site for metastasis, even if >30 different primary tumor entities have been described to metastasize to the pancreas. More than half of all resected metastasis in the pancreas are from renal cell carcinoma (RCC). RCC demonstrates a particular capacity to metastasize to nearly any site in the body-including uncommon sites like the tongue, salivary glands, spleen, testes, and pancreas-and, have remarkable plasticity and specific molecular trajectories with clinical implications. Cancer cells have a propensity to metastasize to specific organ sites, such as the lungs, liver or skeleton, called "organotropism" and the inherent tumor biology as well as the concept of 'oligometastatic' disease is still controversial and conflicting. Pancreatic metastasis has a very different biology from other RCC metastatic sites. Clinical observations suggest an indolent biology that warrants further investigation. Survival times are very long and approaching up to 10 years in recent series. In this paper we discuss the specific situation of pancreatic metastasis from RCC, the relation to oligometastasis and organotropism and how this can be viewed as a model to better understand cancer biology.

Background: Neutrophil infiltration in tumors and tumor-draining lymph nodes (TDLNs) influences oral squamous cell carcinoma (OSCC) progression and metastasis. Neutrophils can exhibit an immunosuppressive phenotype, with CD18 and CD36 potentially linked to this. This study characterizes CD18/CD36 expression on neutrophils from different OSCC microenvironments and their association with metastasis.

Methods: We assessed CD18 and CD36 expression on neutrophils from OSCC tumors, TDLNs, and healthy lymph nodes using flow cytometry. We also examined whether co-culture with the CAL27 oral cancer cell line influenced CD18/CD36 expression in blood neutrophils from healthy donors.

Results: Neutrophils from OSCC tumors and TDLNs exhibited higher CD18 expression than those from healthy lymph nodes, while CD36 was increased only in OSCC tumors. The highest CD18/CD36 expression was observed in metastasis. In vitro co-culture with CAL27 cells prolonged neutrophil survival and enhanced CD18 expression but had no impact on CD36 levels.

Conclusion: Increased CD18/CD36 expression in OSCC neutrophils, particularly in metastasis, suggests their role in tumorigenesis. The elevated CD18 expression in TDLNs highlights enhanced neutrophil-lymphocyte interactions during cancer progression. Our in vitro findings underscore the ability of cancer cells to modulate neutrophil lifespan and phenotype, though this may not fully replicate the tumor microenvironment. This study provides insight into neutrophil contributions to OSCC progression and supports their potential as therapeutic targets.

Mediastinal oligometastases represent a clinical and technical challenge, due to the need to combine optimal treatment with the risk of severe toxicity. In this retrospective multicentre experience, we report the data of a cohort of patients treated with stereotactic body radiotherapy (SBRT) for oligometastatic mediastinal lymph-nodes. Inclusion criteria of the study were: written informed consent for the treatment, ECOG PS ≤ 2, diagnosis of oligometastatic mediastinal lymph-nodes up to 5 lesions being the mediastinum the only active site of disease, patients treated with radiotherapy schedules applying a minimum 6 Gy per fraction. Prior radiotherapy to the mediastinum was not considered as an exclusion criterion. A total of 63 lymph-node metastases in 49 patients with median age of 69.5 years (range 47-83 years) received SBRT between September 2020 and April 2024, for a median total dose of 30 Gy (range 21-50 Gy) in 5 fractions (range 3-5). With a median follow-up of 15 months, 1- and 2-year local control rates were 96.9% and 91.8%, while distant progression-free survival rates were 66.7% and 30.2%. Median time to new systemic therapy was 12 months, while 1- and 2-year polymetastatic-free survival (PMFS) and overall survival (OS) were respectively 78% and 64%, and 86.2% and 75.8%. At statistical analysis, patients who develop a further oligoprogression treated with a second course of SBRT have a longer time to new systemic treatment (p = 0.017), being genitourinary and gynecological malignancies related to improved PMFS and OS at univariate analysis. Only one late G3 adverse event was observed, consisting of dysphagia treated with intravenous steroids. In our series, SBRT for oligometastatic mediastinal lymph-nodes was safe with a single G3 late adverse event, with promising results in terms of local control and time to activation of a new systemic therapy.