Clinical & Experimental Metastasis最新文献

The abscopal effect (AE) in oncology, where localized radiation therapy (RT) triggers a systemic anti-tumor immune response, holds great promise for revolutionizing cancer treatment. Emerging evidence suggests microRNAs (miRNAs), small non-coding RNAs, are essential in mediating the intricate interactions among the tumor, immune system, and tumor microenvironment underlying the AE. miRNAs, both within the tumor and circulating as exosomal cargo, can regulate gene expression to modulate the tumor microenvironment, enhance antigen presentation, and activate anti-tumor immunity. This miRNA-mediated intercellular communication can influence the radiation response, including tumor radiosensitivity, DNA damage repair, and apoptosis. Targeting specific miRNAs or leveraging miRNA-based therapies may sensitize tumors to radiation-induced immune responses, leading to more robust and durable AEs. Understanding the epigenetic regulation of the AE by miRNAs offers novel strategies to harness this phenomenon for improved cancer outcomes. Exploring the intersection of miRNAs, radiation, and the immune system holds the promise of developing more effective, personalized radiotherapy approaches that can unleash the body's defenses against metastatic disease. Unlocking the power of miRNA-mediated signaling may be the important key to unlocking the full potential of AE in the field of cancer treatment.

Fumarate hydratase-deficient renal cell carcinoma (FHdRCC) has been classified under the new category of molecularly defined RCCs according to the WHO classification 2022. Although rare, FHdRCC is an aggressive malignancy with a high metastatic potential and poor prognosis, even at early stages. Due to its low incidence, no standard therapeutic regimen has been established to date. Several phase 2 clinical trials are evaluating combinations of targeted therapies in patients with advanced/metastatic disease. These include immune checkpoint inhibitors (nivolumab, tislelizumab, sintilimab, avelumab), multi-tyrosine kinase inhibitors (cabozantinib, erlotinib, lenvatinib, axitinib, vandetanib), and PARP inhibitors (talazoparib). The most promising combinations are nivolumab/cabozantinib (N = 5, objective response rate (ORR): 100%), lenvatinib/tislelizumab (N = 14, ORR: 93.3%), bevacizumab/erlotinib (N = 43, ORR: 72%), and sintilimab/axitinib (N = 19, ORR: 63.1%). In this review, we will provide a detailed overview of ongoing clinical trials, highlighting the roles of metabolic and epigenetic reprogramming, as well as pro- oncogenic signaling, which together form the backbone for emerging novel targeted treatment strategies. Targeting these specific signaling pathways will shift the therapeutic landscape toward personalized medicine in metastatic FHdRCC.

Ovarian cancer remains a significant challenge in oncology due to its aggressive nature, late-stage diagnosis, and high rates of chemoresistance, particularly to platinum-based therapies like cisplatin. The epithelial-mesenchymal transition (EMT) is a key driver of ovarian cancer metastasis and drug resistance, highlighting the need for novel therapeutic strategies. Cold atmospheric plasma (CAP) and plasma-activated liquids (PAL), including plasma-activated medium (PAM) and saline (PAS), have emerged as promising anticancer agents, generating reactive oxygen and nitrogen species (RONS) that selectively target cancer cells. This study investigates the potential of PAL to inhibit the invasion and metastasis of cisplatin-resistant ovarian cancer cells and explores its synergistic effects with cisplatin. In vitro, PAM reduced proliferation, migration, and invasion of cisplatin-resistant ovarian cancer cells (A2780/DDP and SKOV3/DDP) while downregulating EMT-related proteins (N-cadherin, β-catenin, vimentin). H₂O₂ in PAM inhibit the PI3K/AKT/GSK3β pathway, promoting degradation of EMT regulators Snail, Slug, and β-catenin. Combining PAM with cisplatin enhanced therapeutic efficacy, reducing cell viability and metastatic potential. In vivo studies using an orthotopic mouse model further confirmed that PAS combined with low-dose cisplatin effectively suppressed tumor growth and metastasis with minimal side effects. These findings underscore the potential of PAL as an adjuvant therapy for cisplatin-resistant ovarian cancer, offering a novel approach to overcome drug resistance and inhibit metastasis. Future research should focus on optimizing treatment protocols and elucidating the molecular mechanisms underlying the synergistic effects of PAL and cisplatin.

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.