Clinical & Experimental Metastasis最新文献

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.

Objective: Aberrant expression of CD276 has been reported in malignant tumors. However, the exact role and mechanisms of CD276 influence the progression of esophageal squamous cell carcinoma (ESCC) still need to be understood.

Methods: Bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus databases, along with immunohistochemistry staining, was used to explore the expression patterns of CD276 in ESCC. Cell counting kit-8 and Transwell assays were employed to evaluate the effects of CD276 expression on tumor cell proliferation and motility. Western blotting and Transwell assays were used to explore the potential pathways through which CD276 mediates the progression of ESCC. Moreover, the in vivo role of CD276 in tumor progression was investigated by establishing a lung metastasis mouse model.

Results: A significant upregulation of CD276 was observed in ESCC tissues compared to adjacent tissues. The inhibition of CD276 had no evident impact on ESCC cell proliferation but notably hindered their migratory and invasive properties and the expression of epithelial-mesenchymal transition (EMT) markers. Inversely, overexpressing CD276 led to an upregulation of EMT markers, underscoring the capacity of CD276 to amplify the motility of ESCC cells. Furthermore, CD276 was found to enhance the migratory and invasive abilities of ESCC cells by activating the TGF-β/SMAD signaling but not the PI3K/AKT pathway. In vivo studies demonstrated that CD276 facilitates pulmonary metastasis.

Conclusion: CD276 is significant upregulation in ESCC tissues and facilitates the EMT process in ESCC cells via the TGF-β/SMAD signaling, thus promoting the progression of ESCC.

Bioluminescence imaging (BLI) is a non-invasive state-of-the-art-method for longitudinal tracking of tumor cells in mice. The technique is commonly used to determine bone metastatic burden in vivo and also suitable ex vivo to detect even smallest bone micro-metastases in spontaneous metastasis xenograft models. However, it is unclear to which extent ex vivo BLI correlates with alternative methods for metastasis quantification. Here, we compared ex vivo BLI, human DNA-based Alu-qPCR, and histology for the quantification of bone vs. lung metastases, which are amongst the most common sites of metastasis in prostate cancer (PCa) patients and spontaneous PCa xenograft models. Data from 93 immunodeficient mice were considered, each of which were subcutaneously injected with luciferase/RGB-labeled human PCa PC-3 cells. The primary tumors were resected at ~ 0.75 cm³ and mice were sacrificed ~ 3 weeks after surgery and immediately examined by ex vivo BLI. Afterwards, the right lungs and hind limbs with the higher BLI signal (BLI^Hi bone) were processed for histology, whereas the left lung lobes and hind limbs with the lower BLI signal (BLI^Lo bone) were prepared for Alu-qPCR. Our data demonstrate remarkable differences in the correlation coefficients of the different methods for lung metastasis detection (r ~ 0.8) vs. bone metastasis detection (r ~ 0.4). However, the BLI values of the BLI^Hi and BLI^Lo bones correlated very strongly (r ~ 0.9), indicating that the method per se was reliable under identical limitations; the overall level of metastasis to contralateral bones was astonishingly similar. Instead, the level of lung metastasis only weakly to moderately correlated with the level of bone metastasis formation. Summarized, we observed a considerable discrepancy between ex vivo BLI and histology/Alu-qPCR in the quantification of bone metastases, which was not observed in the case of lung metastases. Future studies using ex vivo BLI for bone metastasis quantification should combine multiple methods to accurately determine metastatic load in bone samples.

Rationale

Colorectal Cancer (CRC) represents the third most common type of cancer in Germany and the second most common cancer-related cause of death worldwide. Distant metastases are still the main limit for patient survival. While liver metastases as well as peritoneal carcinomatosis can often either be resected or treated with systemic therapy, little options remain for brain metastases. Additionally, a number of studies has already investigated hepatic, peritoneal, pulmonary as well as continuing distant metastases in colorectal cancer. Yet, with respect to tumor biology and brain metastases, little is known so far.

Material and methods

Two cohorts, M0 without distant spread and BRA with brain metastases were build. RNA was isolated from paraffin embedded specimen. Gene expression was performed by an RNA NanoString-Analysis using the nCounter® PanCancer Progression Panel by NanoString-Technologies (Hamburg, Germany). Results were analysed by principal component analysis, gene expression and pathway analysis using commonly available databases such as KEGG as benchmark for comparison.

Results

We were able to determine a gene signature that provides a sophisticated group separation between M0 and BRA using principal component analysis. All genes with strong loading characteristics on principal component 1 were cross-referenced with the subsequently performed accurate gene set enrichment analysis (GSEA). The GSEA revealed a clear dysregulation of the TGFβ pathway in compared cohorts M0 and BRA. Interestingly, the targeted pathways analysis of the identified genes confirmed that in fact almost all strong loading genes of PC1 play a role in the TGFβ pathway.

Conclusion

Our results suggest the TGFβ pathway as a crucial player in the development of brain metastases in primary CRC. In some types of colorectal cancer, downregulation of the TGFβ pathway might hinder primary colorectal cancer to metastasize to the nervous system. While the paradoxical functioning of the TGFβ pathway is still not fully understood, these shed light on yet another clinical implication of this complex pathway.

Lung cancer is a type of cancer that can metastasize to the lungs, brain, bones, liver, adrenal glands, and other organs; however, the occurrence of brain metastases is the most common event. Symptoms of brain metastasis include motor dysfunction, mental dysfunction, seizures, headaches, nausea, and vomiting, and significantly reduce the quality of life of cancer patients. Brain metastases are a poor prognostic factor, and controlling them is extremely important for prolonging prognosis and improving the quality of life. Currently, local surgery and radiotherapy are recommended for their treatment. However, recently, cancer treatments using molecular-targeted drugs and immune checkpoint inhibitors have been introduced, which may also be effective against brain metastases. Therefore, it is necessary to determine whether local or systemic therapy is optimal for each case. In this review, we focus on recent findings regarding drug therapy in treating brain metastases from advanced non-small cell lung cancer.

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

Abstract

Lymph nodes (LNs) are principal orchestrators of the adaptive immune response, yet in the context of malignancy, they are typically the first sites of metastasis. When tumors spread to LNs, they alter the immune repertoire, ultimately reconditioning it in a manner that suppresses anti-tumor immunity and promotes further metastatic dissemination. Conversely, activation of anti-tumor immunity within LNs is essential for immunotherapy, suggesting clinical approaches to radiotherapy in LNs and lymphadenectomy may need to be reconsidered in the context of immune checkpoint blockade (ICB). Herein, we discuss our understanding of the immune remodeling that coincides with LN metastasis as well as recent clinical studies exploring neoadjuvant immunotherapy and the roles of LNs in treatment of solid organ malignancies.

The prevailing treatment stratagem in cancer therapy still challenges the dilemma of a probable metastatic spread following an initial diagnosis. Including an anti-metastatic agent demands a significant focus to overrule the incidence of treatment failures. Adrenergic stimulation underlying the metastatic spread paved the way for beta blockers as a breakthrough in repurposing as an anti-metastatic agent. However, the current treatment approach fails to fully harness the versatile potential of the drug in inhibiting probable metastasis. The beta blockers were seen to show a myriad of grip over the pro-metastatic and prognostic parameters of the patient. Novel interventions in immune therapy, onco-hypertension, surgery-induced stress, induction of apoptosis and angiogenesis inhibition have been used as evidence to interpret our objective of discussing the potential adjuvant role of the drug in the existing anti-cancer regimens. Adding weight to the relative incidence of onco-hypertension as an unavoidable side effect from chemotherapy, the slot for an anti-hypertensive agent is necessitated, and we try to suggest beta-blockers to fill this position. However, pointing out the paucity in the clinical study, we aim to review the current status of beta blockers under this interest to state how the drug should be included as a drug of choice in every patient undergoing cancer treatment.

The objective of this study was to analyze the expression and prognostic role of the tight junction protein occludin in high-grade serous carcinoma (HGSC). Occludin protein expression by immunohistochemistry was analyzed in 602 HGSC (417 effusions, 185 surgical specimens). Expression in mesothelioma (n = 87; 45 effusions, 42 surgical specimens) was studied for comparative purposes. Occludin protein expression was found in 587/602 (98%) HGSC vs. 40/87 (46%) mesotheliomas and was predominantly limited to < 5% of cells in the latter (p < 0.001). Occludin was additionally overexpressed in HGSC effusions compared to surgical specimens (p < 0.001) and was overexpressed in post-chemotherapy effusions compared to chemo-naive effusions tapped at diagnosis (p = 0.015). Occludin expression in HGSC surgical specimens was associated with poor chemoresponse (p < 0.001) and primary resistance (p = 0.001). Expression in effusions and surgical specimens was unrelated to survival (p > 0.05). In conclusion, occludin expression is higher in HGSC compared to mesothelioma, and this protein is overexpressed in HGSC effusions, possibly reflecting changes in adhesion related to anchorage-independent growth in this microenvironment. Overexpression in post-chemotherapy compared to chemo-naïve effusions suggest a role in disease progression. Occludin expression in surgical specimens may be related to chemoresistance.