High Rate Of Lung Metastasis Research Articles

Mouse Models of HER2+ Human Breast Cancer: A Literature Review

Introduction: HER2+ breast cancer (BC) makes up 15-20% of BC cases, where HER2 overexpression drives BC progression via proliferative signals. Targeted therapies inhibit HER2's activity but face challenges like resistance and metastasis. Thus, HER2+ BC is a developing research area where many preclinical studies are being conducted, and mice are often used due to their genetic and physiological similarities to humans. This study aims to review and compare existing mouse models to determine the best model of HER2+ BC. Methods: A literature search on PubMed in February 2024 using search terms including HER2, neu, neuNT, MMTV, and mammary tumors identified 16 primary research articles that used Neu-overexpressing mice. The papers were categorized under five models: MMTV-Neu, MMTV-NeuNT, FloxNeo-NeuNT, MMTV-NIC, and MMTV-HER2. Results: Among examined studies, Andrechek et al.'s FloxNeo-NeuNT model had the longest average tumor onset at 447 days, while Kuang et al.'s MMTV-NIC had the shortest at 126 days. Ursini-Segal et al.'s MMTV-NIC mice showed 100% mammary tumor incidence. Most models resulted in mammary adenocarcinomas, with lung metastases commonly observed, especially in papers that used MMTV-NIC. Discussion: Human HER2+ BC is commonly adenocarcinoma and often metastasizes to lungs, bones, liver, and brain. The mouse models were also found to be adenocarcinomas, but they primarily showed lung metastasis, possibly due to insufficient tumor detection methods for brain and bone metastasis. Neu copy numbers in Andrechek et al.’s FloxNeo-NeuNT model also align with findings on HER2 copy number amplification in human HER2+ BC. Conclusion: We have found that MMTV-NIC is the optimal mouse model for HER2+ BC research due to its short latency, 100% tumor incidence, and high rate of lung metastasis.

Resveratrol Loaded by Folate-Modified Liposomes Inhibits Osteosarcoma Growth and Lung Metastasis via Regulating JAK2/STAT3 Pathway.

Osteosarcoma is a malignant bone tumor with a high rate of lung metastasis and mortality. It has been demonstrated that resveratrol can inhibit tumor proliferation and metastasis, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare folate-modified liposomes loaded with resveratrol to investigate its anti-osteosarcoma effect in vitro and in vivo. We prepared and characterized resveratrol liposomes modified with folate (denoted as, FA-Res/Lps). The effects of FA-Res/Lps on human osteosarcoma cell 143B proliferation, apoptosis, and migration were investigated by MTT, cell cloning, wound-healing assay, transwell, and flow cytometry. A xenograft tumor and lung metastasis model of osteosarcoma was constructed to study the therapeutic effects of FA-Res/Lps on the growth and metastasis of osteosarcoma in vivo. The FA-Res/Lps were prepared with a particle size of 118.5 ± 0.71 and a small dispersion coefficient of 0.154 ± 0.005. We found that FA-modified liposomes significantly increased resveratrol uptake by osteosarcoma cells 143B in flow cytometric assay, resulting in FA-Res/Lps, which inhibit tumor proliferation, migration and induce apoptosis more effectively than free Res and Res/Lps. The mechanism of action may be associated with the inhibition of JAK2/STAT3 signaling. In vivo imaging demonstrated that FA-modified DiR-modified liposomes significantly increased the distribution of drugs at the tumor site, leading to significant inhibition of osteosarcoma growth and metastasis by FA-Res/Lps. Furthermore, we found that FA-Res/Lps did not cause any adverse effects on mice body weight, liver, or kidney tissues. Taken together, the anti-osteosarcoma effect of resveratrol is significantly enhanced when it is loaded into FA-modified liposomes. FA-Res/Lps is a promising strategy for the treatment of osteosarcoma.

Occam’s Razor-Inspired Nb2C delivery platform potentiates breast cancer therapy and inhibits lung metastasis

Breast cancer exhibits a high rate of lung metastasis and is one of the leading causes of cancer-related mortality in women. Hence, it is critical to develop innovative therapeutic strategies to combat breast cancer and lung metastasis. The physical and optical properties of niobium carbide (Nb2C) nanosheets endow them with excellent photothermal conversion properties and the capacity for drug delivery, making them ideal for photothermal therapy (PTT) in breast cancer and its lung metastasis. To explore a new synergistic strategy for subcutaneous tumor ablation and lung metastasis inhibition in breast cancer, an Occam’s Razor-inspired nanocomposite (Nb2C-BBR) was fabricated based on functionalized Nb2C nanosheets and berberine (BBR), a natural inhibitor that regulates metastasis-related proteins in the tumor microenvironment. The Nb2C nanosheets were ultrathin (thickness of ∼ 124 nm), could be endocytosed into subcellular organelles, showed desirable photothermal-conversion efficiency (38 % and 59 % at 808 nm and 1064 nm, respectively), and achieved multi-modal imaging in the near-infrared (NIR-II) biowindow. With a size of 130.4 nm, the Nb2C-BBR nanocomposites exhibited favorable biocompatibility and reduced the dose of Nb2C nanosheets required under NIR-II irradiation while maintaining photothermal performance and anticancer efficacy. Combined chemotherapy and PTT with the Nb2C-BBR nanocomposites not only eradicated cancer cells notably but also significantly suppressed cell proliferation by activating the mitochondrial apoptotic pathway. By regulating the expression of proteins associated with the epithelial-mesenchymal transition and extracellular matrix both in vitro and in vivo, Nb2C-BBR nanocomposites significantly inhibited the migration and invasion of breast cancer cells following NIR-II irradiation. The functionalized nanoplatform for synergistic therapy efficiently destroyed cancer cells, inhibited metastasis, and induced only minor local tissue damage, demonstrating its potential as a treatment approach for metastatic tumors.

The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets

Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.

Chemotherapy versus chemoradiotherapy in borderline resectable and locally advanced pancreatic adenocarcinoma.

The role of radiotherapy in borderline resectable (BRPC) and locally advanced pancreatic carcinoma (LAPC) remains controversial. In our study, we retrospectively evaluated 48 patients with BRPC (14; 29.2%) and LAPC (34; 70. 8%) who underwent 6-8 cycles of induction mFOLFIRINOX chemotherapy alone (23; 47.9%) or 4-6 cycles of mFOLFIRINOX followed by hypofractionated radiotherapy (up to the total dose of 39.9 Gy in 15 fractions) (25; 52.1%). Survival parameters were evaluated using the Gehan-Breslow-Wilcoxon Test and compared by using the long-rank test. The addition of radiotherapy was not associated with better survival (16.9 months for chemotherapy only versus 15.9 months for the combined therapy; p=0.486), as well as for both subgroups (13.5 months vs. 18.3 months; p=0.679) and (20.7 months vs. 13.8 months; p=0.425) for BRPC and LAPC, respectively. A higher resection rate was seen in the BRPC group compared to the LAPC group (43% vs. 17.6%, respectively). Our study revealed a significantly higher rate of lung metastases in patients after the combination therapy compared to those treated by chemotherapy only (19% vs. 0%, respectively; p=0.045). Such a borderline result, however, prevents us from drawing clear conclusions about whether this is an artifact caused by the low number of patients or whether radiotherapy leads to a selection of stem cells with a predilection to the generalization to the lungs.

TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling

Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.

MIR205 host gene (MIR205HG) drives osteosarcoma metastasis via regulating the microRNA 2114-3p (miR-2114-3p)/twist family bHLH transcription factor 2 (TWIST2) axis

ABSTRACT Osteosarcoma (OS) is an aggressive malignant tumor with a high rate of lung metastasis and a lack of therapeutic targets. Although the anomalous expression of long non-coding RNA (lncRNA) has been extensively documented in human cancer, its contribution to OS metastasis remains poorly understood. In this study, we found that MIR205 host gene (MIR205HG) was significantly elevated in human OS tissues, especially in metastatic OS tissues. Stable knockdown of MIR205HG inhibited OS cell invasion and lung metastatic foci formation, but did not affect cell viability. The vast majority of MIR205HG was situated in the cytosol, and served as a competing endogenous RNA (ceRNA) that directly bound to microRNA 2114–3p (miR-2114-3p), resulting in increased twist family bHLH transcription factor 2 (TWIST2) level. Pre-clinically, high MIR205HG was linked with dismal overall and relapse-free survival. Functionally, the attenuated cell invasion caused by MIR205HG knockdown was effectively rescued by miR-2114-3p silencing or TWIST2 overexpression. Overall, our findings suggest that the previously uncharacterized regulatory axis of MIR205HG/miR-2114-3p/TWIST2 plays a critical role in promoting OS metastasis, which implies a potential therapeutic target in OS patients with metastasis.

Quercetin augments apoptosis of canine osteosarcoma cells by disrupting mitochondria membrane potential and regulating PKB and MAPK signal transduction.

Osteosarcoma is a mesenchymal malignant bone tumor accompanied by a high rate of lung metastasis and short survival in dogs. Although various therapies have been reported, the etiological mechanism of osteosarcoma remains undetermined and the development of novel therapeutic agents is warranted. In this study, we have reported the diverse functions of quercetin, one of the well-known flavonoid, in D-17 and DSN (canine osteosarcoma) cell lines. Current results indicate that quercetin decreases proliferative properties and increases programmed cell death, in addition to altering the cell cycle, mitochondrial depolarization, level of reactive oxygen species, and concentration of cytoplasmic calcium in both cells. Furthermore, it was observed that quercetin suppresses phosphorylation of AKT, P70S6K, and S6 proteins and upregulates phosphorylation of ERK1 or 2, P38, c-Jun N-terminal kinase, and P90RSK proteins in both cell lines. Collectively, we suggest that quercetin can be used as a pharmacological agent for suppressing the proliferation and inducing the apoptosis of canine osteosarcoma cells.

Forecast of actin-binding proteins as the oncotarget in osteosarcoma - a review of mechanism, diagnosis and therapy.

Osteosarcoma (OS) is the most common bone malignant tumor with a high rate of lung metastasis and principally emerges in children and adolescents. Although neoadjuvant chemotherapy is widely used around the world, a high rate of chemoresistance occurs and frequently generates a poor prognosis. Therefore, finding a new appropriate prognostic marker for OS is a valuable research direction, which will give patients a better chance to receive proper therapy. Actin-binding proteins (ABPs) are a group of proteins that interact with actin cytoskeleton and play a crucial role in the regulation of the cell motility and morphology in eukaryotes. Meanwhile, ABPs also act as a bridge between the cytomembrane and nucleus, which transmit the outside-in and inside-out signals in cytoplasm. Furthermore, ABPs alter the dynamic structure of actin and regulate the invasion and metastasis of cancer. Hence, ABPs have a wide application in predicting the prognosis, and may be new targets, in tumor therapy. This review focuses on a series of ABPs and discusses their modulatory functions. It provides a new insight into the classification of ABPs’ functions in the process of invasion and metastasis in OS and illuminates the potential ability in predicting the prognosis of OS patients.

ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway

Background/Aims: Gain-of-function of mutant p53 is associated with a high rate of lung metastasis in osteosarcoma. To investigate the mechanism of mutant p53-induced osteosarcoma metastasis, expression array analysis was performed, comparing non-metastatic osteosarcomas from p53+/- mice with metastatic osteosarcomas from p53R172H/+ mice. Onzin (Plac8) was identified as one of the genes upregulated in p53R172H/+ mouse metastatic osteosarcomas. Accordingly, we investigated the role of ONZIN in human osteosarcoma metastasis. Methods: ONZIN function and its downstream targets were examined in osteosarcoma cell lines. Assays related to tumorigenesis and metastasis, including cell migration, invasion, clonogenic survival, and soft agar colony formation, were performed in osteosarcoma cells. Additionally, mouse xenograft models were used to examine the role of ONZIN overpression in tumorigenesis in vivo. Lastly, 87 osteosarcoma patients were recruited to investigate the clinical relevance of ONZIN overexpression in metastasis and prognosis. Results: ONZIN overexpression enhanced osteosarcoma cell proliferation, clonogenic survival, migration, and invasion independent of p53 status. Furthermore, ONZIN overexpression induced CXCL5 upregulation and resulted in increased ERK phosphorylation, which contributed to more aggressive osteosarcoma metastatic phenotypes. More importantly, overexpression of ONZIN in human osteosarcoma patients was closely associated with lung metastasis, poor prognoses, and survival. Conclusions: Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis.

Hyperbranched polymer drug delivery treatment for lung metastasis of salivary adenoid cystic carcinoma in nude mice.

Salivary adenoid cystic carcinoma (SACC) is associated with a high rate of lung metastasis. When lung metastasis occurs, the effects of traditional chemotherapy on SACC are poor. Hyperbranched polymer drug delivery (degradable hyperbranched polyglycerols, dHPGs) can be used as a strategy to load several drugs, and obtain beneficial effects on SACC lung metastasis through enhanced permeability and retention. In the present study, hydroxycamptothecin (HPT)-conjugated dHPG (dHPG-HPT) was synthesized and its effects on SACC xenografts in the lungs of nude mice were evaluated. SACC cells with a high potential for pulmonary metastasis (SACC-LM cells) were injected into the tail vein of mice, establishing a nude mouse model. The mice were randomly divided into the three following groups: Control, HPT and dHPG-HPT. Saline (control), HPT or dHPG-HPT were injected into the mice. After two weeks, the mice were euthanized and their lungs were removed. The lungs were paraffin-embedded for hematoxylin and eosin, and immunohistochemical staining analyses. Primary antibodies directed against vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase 9 (MMP9) were used. Gross observation demonstrated that the volumes of SACC lung metastasis nodules were significantly decreased in the dHPG-HPT group compared with the control and HPT groups. Immunohistochemical analysis revealed a lower expression of VEGF, CD34, PCNA and MMP9 in the dHPG-HPT group. The results of the current study suggest that dHPG-HPT can suppress the growth of SACC xenografts in nude mice, providing a theoretical basis for macromolecular drug delivery-based treatment of SACC.

Giant cell tumour of bone: A demographic study from a tumour unit in South Africa

INTRODUCTION: Giant cell tumour of bone (GCT) is a rare primary bone tumour. Little is known about the epidemiology of this tumour in South Africa as most demographic information is based on research from Asia, Europe and North America. This research aims to raise awareness and promote early recognition of these tumours. Materials and methods: A retrospective analysis was conducted of all patients with biopsy-confirmed GCTs that presented between January 2010 and December 2014. Information pertaining to patient demographics, tumour location, treatment and outcome was recorded and analysed. RESULTS: Twenty-two patients were included in the study. The mean age of patients was 32.4 years (range 12-63), and a slight male predominance (1.2:1) was observed. Tumours were mainly located at the end of long bones (91%) with the distal femur and proximal tibia being most commonly affected (55%). Two patients (9%) were diagnosed with primary malignant giant cell tumours. We observed a higher rate of lung metastases (18%) than previously reported. The median tumour volume was significantly higher in patients who developed lung metastases (467.4 cm3 vs 137.8 cm3; p=0.03). Three of the patients with lung metastases were HIV-positive (odds ratio [OR] = 10.5, 95% confidence interval [CI] = 0.84-130.66, p=0.076). All patients were treated surgically with extended curettage, local adjuvant therapy, polymethyl methacrylate (PMMA) and internal fixation or en-bloc resection with prosthetic or osteochondral allograft replacement. CONCLUSION: Giant cell tumours of bone are uncommon. Demographics from South Africa emulate international statistics. No recurrence of GCTs was observed in our cohort despite the relatively large tumours at time of presentation compared to international literature that report recurrence rates of approximately 2%. The incidence of metastases and primary malignant GCT was higher than in previous reports. The association of these findings with HIV infection warrants further investigation. Metastases appear to be associated with the size of the primary tumour.

Mutational analysis and clinical correlation of 185 consecutive metastatic colorectal patients: Similarities and differences between colon and rectal patients.

3536 Background: Cancers of the colon and rectum are largely considered to be molecularly comparable diseases, harboring activating mutations in KRAS, BRAF, NRAS, and PIK3CA. These mutations have an impact on both prognosis and therapeutic options. In this study, we used a multiplexed clinical assay (SNaPshot) (Dias-Santagata D, EMBO Mol Med. 2010 May;2(5):146-58) performed on nucleic acid derived from formalin-fixed tissue which tests for 120 previously described mutations across 13 cancer genes and examined the relationship with clinical features and disease site. Methods: 185 consecutive metastatic colorectal patients were identified in our clinic and underwent testing with SNaPshot in an IRB approved protocol. Mutational analysis was performed across 13 genes, including KRAS codons 12 and 13, NRAS codons 12, 13, and 61, BRAF codon 600, and PIK3CA codons 88, 542, 545-546, 1047, and 1049. Patient charts were reviewed for demographic data, primary site, metastatic sites at presentation and last follow-up. Fisher’s exact test was performed to determine statistical significance. Results: Of the 185 patients, 51 (38%) had a rectal primary and 134 (62%) had a colon primary. Median age was 55 years (29-83). There were 78 females (42%). Comparative mutation rate for rectal vs colon primary (respectively) was: KRAS -33% vs 36% (NS), BRAF – 2% vs 11% (P=0.07), PIK3CA - 12% vs 13% (NS), dual PIK3CA/KRAS- 8% vs 5% (NS), and NRAS - 14% vs 1% (P=0.001). The single colon patient with an NRAS mutation had a sigmoid colon primary. Rectal primary was associated with a higher rate of lung metastases at presentation (43%) than colon (21%), P=0.003. NRAS mutation was associated with an 88% (7/8) rate of lung metastases and a 0% rate of bone and CNS metastases. Conclusions: Rectal and colon patients have similar rates of KRAS and PIK3CA mutations. However, BRAF mutations are more common in colon cancer. NRAS mutations are exclusively found in rectosigmoid cancers and may have a different biology than other colorectal cancers. These data suggest that primary tumor location may provide a means to enrich a population for a genotype-directed study.

Synovial sarcomas exhibit a high rate of lung metastasis following local control by surgery and radiation therapy

Synovial sarcomas exhibit a high rate of lung metastasis following local control by surgery and radiation therapy