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Xenograft models of brain metastasis and primary breast cancer. (a) For models of brain metastasis, human breast cancer (231-Luc, HER2-60, and HER2-90) or melanoma (MeWo, WM3734) cell lines (or PBS as a control) were injected into the left ventricle of female immunodeficient mice. For models of primary breast cancer, human 231-Luc or HCC1937 cells were orthotopically injected into mammary fat pads. (b) Hematoxylin-eosin staining of mouse brain tissue with metastases formed by 231-Luc, MeWo, or WM3734 cells. Arrows indicate human metastatic cancer cells. Scale bars, 200 μm.
Source publication
Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanism...
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Citations
... In this study, high expression of PLLP (Plasmolipin) was associated with poor prognosis in patients with SCLC. PLLP has been found to be up-regulated in brain tissues harboring metastases [86]; however, the clinical significance of PLLP in cancer has not yet been clarified. PSRC1 (Proline and Serine Rich Coiled-Coil 1) encodes a tumor suppressor protein p53-and DNA-damage down-regulated protein that plays an important role in mitosis and exhibits oncogenic characteristics [87]. ...
Simple Summary
Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma with a poor prognosis, accounting for approximately 15% of lung cancer cases. Acquired resistance to standard chemotherapy is quite common in SCLC patients, and the survival benefit of surgery and the selection of surgical candidates are still controversial. This highlights the necessity of identifying predictive biomarkers that can serve to select patients who will benefit from various treatments and discovering novel molecular targets for SCLC treatment. In this study, for the first time, the association between tumoral transcriptional changes and prognosis was examined, and a novel multigene prognostic risk signature with strong discriminatory power was constructed and validated to predict the overall survival of SCLC patients who have undergone curative-intent surgical resection. The risk signature worked better than existing clinical and demographic parameters in predicting overall survival in patients with resected SCLC. Prognostic genes were predicted to have roles in pathways including regulation of transcription, cell cycle, cell metabolism, and angiogenesis.
Abstract
Small cell lung cancer (SCLC) is a malignancy with a poor prognosis whose treatment has not progressed for decades. The survival benefit of surgery and the selection of surgical candidates are still controversial in SCLC. This study is the first report to identify transcriptomic alterations associated with prognosis and propose a gene expression-based risk signature that can be used to predict overall survival (OS) in SCLC patients who have undergone potentially curative surgery. An integrative transcriptome analysis of three gene expression datasets (GSE30219, GSE43346, and GSE149507) revealed 1734 up-regulated and 2907 down-regulated genes. Cox-Mantel test, Cox regression, and Lasso regression analyses were used to identify genes to be included in the risk signature. EGAD00001001244 and GSE60052-cohorts were used for internal and external validation, respectively. Overall survival was significantly poorer in patients with high-risk scores compared to the low-risk group. The discriminatory performance of the risk signature was superior to other parameters. Multivariate analysis showed that the risk signature has the potential to be an independent predictor of prognosis. The prognostic genes were enriched in pathways including regulation of transcription, cell cycle, cell metabolism, and angiogenesis. Determining the roles of the identified prognostic genes in the pathogenesis of SCLC may contribute to the development of new treatment strategies. The risk signature needs to be validated in a larger cohort of patients to test its usefulness in clinical decision-making.
... PTPRQ encodes a protein from a family involved in important processes such as cell proliferation, differentiation, and survival [37,38]. Increased expression of PTPRQ was observed in metastatic tumors from mice [39]. Consistently, mutations resulting in the upregulation of other protein tyrosine phosphatase receptors have been implicated as a metastatic driver event in colorectal cancer [40] and cervical cancer [41,42]. ...
Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein–protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.
... Less information is available about the expression levels of other MAL-family genes. Using xenografts in nude mouse models of human breast cancer and melanoma metastasis, PLLP was found specifically upregulated in tumor cells that metastasize to the brain [115]. Using IHC staining, CMTM8 was found to be significantly downmodulated or absent in LIHC, LUSC, COAD, READ, ESCA, STAD, and BLCA compared with adjacent normal tissue [116][117][118], but upregulated in PAAD [119]. ...
... Consistent with a role of CMTM8 in cancer progression, CMTM8-depleted human pancreatic cancer PANC-1 cells reduced the formation of metastatic lesions in the lung of nude mice relative to those produced by the parental cells [119]. Using human breast cancer and melanoma cell lines inoculated in nude mice, it was found that PLLP upregulates in cancer cells metastasized to the brain, raising the possibility that PLLP is involved in the colonization of the brain by these types of cancers [115]. ...
The MAL family of integral membrane proteins consists of MAL, MAL2, MALL, PLLP, CMTM8, MYADM, and MYADML2. The best characterized members are elements of the machinery that controls specialized pathways of membrane traffic and cell signaling. This review aims to help answer the following questions about the MAL-family genes: (i) is their expression regulated in cancer and, if so, how? (ii) What role do they play in cancer? (iii) Might they have biomedical applications? Analysis of large-scale gene expression datasets indicated altered levels of MAL-family transcripts in specific cancer types. A comprehensive literature search provides evidence of MAL-family gene dysregulation and protein function repurposing in cancer. For MAL, and probably for other genes of the family, dysregulation is primarily a consequence of gene methylation, although copy number alterations also contribute to varying degrees. The scrutiny of the two sources of information, datasets and published studies, reveals potential prognostic applications of MAL-family members as cancer biomarkers—for instance, MAL2 in breast cancer, MAL2 and MALL in pancreatic cancer, and MAL and MYADM in lung cancer—and other biomedical uses. The availability of validated antibodies to some MAL-family proteins sanctions their use as cancer biomarkers in routine clinical practice.
... Tryptophan hydroxylase gene 2 (TPH2) encodes a protein important for serotonin synthesis pathway. The gene is found to be unregulated in brain tissue with breast cancer or Melanoma metastasis [35]. ...
Background
Locoregional lymph node metastasis represents the first step of metastasis in colorectal carcinomas (CRC). Identifying genetic mutations that may promote metastasis will help optimize the treatment of patients at risk of lymph node metastasis.
Method
Out of 43 identified consented cases of CRCs with and without corresponding metastasis to lymph nodes; 5 cases of CRC with lymph node metastasis were retrieved and matched with another 5 cases of CRC with negative lymph node metastasis. Whole exome sequencing was performed on the primary CRC and their corresponding lymph node metastasis; their genetic profile was compared to the whole-genome sequence of glioblastoma multiforme.
Results
115 variant mutations affecting 110 genes were identified. Focusing on variants with significant biological consequences, 31 of these variant mutations affecting 31 genes with putative role in CRC metastasis were selected. These variants are annotated as missense, splice site or “in frame deletion”.
Conclusion
The identified mutations may be further evaluated clinically as cancer markers for patients at risk for lymph node metastasis.
... Metastasis is the leading cause of cancer therapy failure and poor survival outcomes. It was recently reported that increased PTPRQ expression was specifically associated with metastasis [39]. Sato et al. established a mouse model of brain metastasis cancer by intracardiac injection of cancer cells and then identified the expression of genes related to metastasis by using RNA-seq [39]. ...
... It was recently reported that increased PTPRQ expression was specifically associated with metastasis [39]. Sato et al. established a mouse model of brain metastasis cancer by intracardiac injection of cancer cells and then identified the expression of genes related to metastasis by using RNA-seq [39]. They found that PTPRQ expression was significantly upregulated in the brain microenvironment in association with metastasis. ...
Protein tyrosine phosphatase receptor-type Q (PTPRQ), a member of the type III tyrosine phosphatase receptor (R3 PTPR) family, is composed of three domains including 18 extracellular fibronectin type III (FN3) repeats, a transmembrane helix, and a cytoplasmic phosphotyrosine phosphatase (PTP) domain. PTPRQ was initially identified as a transcript upregulated in glomerular mesangial cells in a rat model of glomerulonephritis. Subsequently, studies found that PTPRQ has phosphotyrosine phosphatase and phosphatidylinositol phosphatase activities and can regulate cell proliferation, apoptosis, differentiation, and survival. Further in vivo studies showed that PTPRQ is necessary for the maturation of cochlear hair bundles and is considered a potential gene for deafness. In the recent two decades, 21 mutations in PTPRQ have been linked to autosomal recessive hearing loss (DFNB84) and autosomal dominant hearing loss (DFNA73). Recent, mutations, deletions, and amplifications of PTPRQ have been observed in many types of cancers, which indicate that PTPRQ might play an essential role in the development of many cancers. In this review, we briefly describe PTPRQ structure, enzyme activity, and focus on the correlation between PTPRQ and human disease. Profound understanding of PTPRQ could be helpful in the identification of new therapeutic targets to treat its associated diseases.
... RNA-sequencing data analysis on the human breast cancer cell line MDA-MB-231 has shown that CXCR4, PLLP, VCAM1, SLC7A11, SLC8A2, and TNFSF4 genes are highly overexpressed in brain metastasis [21]. CHIP-sequencing and RNA-sequencing data analysis performed by Li et al. revealed that many biological pathways promote lung metastasis of breast cancer. ...
Metastatic lesions leading causes of the majority of deaths in patients with the breast cancer. The present study aimed to provide a comprehensive analysis of the differentially expressed genes (DEGs) in the brain (MDA-MB-231 BrM2) and lung (MDA-MB-231 LM2) metastatic cell lines obtained from breast cancer patients compared with those who have primary breast cancer. We identified 981 and 662 DEGs for brain and lung metastasis, respectively. Protein-protein interaction (PPI) analysis revealed seven shared ( PLCB1 , FPR1 , FPR2 , CX3CL1 , GABBR2 , GPR37 , and CXCR4) hub genes between brain and lung metastasis in breast cancer. Moreover, GNG2 and CXCL8 , C3 , and PTPN6 in the brain and SAA1 and CCR5 in lung metastasis were found as unique hub genes. Besides, five co-regulation of clusters via seven important co-expression genes (COL1A2, LUM, SPARC, THBS2, IL1B, CXCL8, THY1) were identified in the brain PPI network. Clusters screening followed by biological process (BP) function and pathway enrichment analysis for both metastatic cell lines showed that complement receptor signalling, acetylcholine receptor signalling, and gastric acid secretion pathways were common between these metastases, whereas other pathways were site-specific. According to our findings, there are a set of genes and functional pathways that mark and mediate breast cancer metastasis to the brain and lungs, which may enable us understand the molecular basis of breast cancer development in a deeper levele to the brain and lungs, which may help us gain a more complete understanding of the molecular underpinnings of breast cancer development.
... When the mechanisms of metastasis in melanoma and breast cancer were studied using mouse models, a substantial increase in expression was observed for CXCR4, PLLP, and TNFSF4 in brain metastases and Tph2, Sspo, and Polas in surrounding tissues [76,77]. A higher invasion potential is known for glioblastoma cells of the pretumoral brain zone (PBZ) as compared with cells of the tumor core (TC). ...
The mechanisms involved in the origin and development of malignant and neurodegenerative diseases are an important area of modern biomedicine. A crucial task is to identify new molecular markers that are associated with rearrangements of intracellular signaling and can be used for prognosis and the development of effective treatment approaches. The proteolipid plasmolipin (PLLP) is a possible marker. PLLP is a main component of the myelin sheath and plays an important role in the development and normal function of the nervous system. PLLP is involved in intracellular transport, lipid raft formation, and Notch signaling. PLLP is presumably involved in various disorders, such as cancer, schizophrenia, Alzheimer’s disease, and type 2 diabetes mellitus. PLLP and its homologs were identified as possible virus entry receptors. The review summarizes the data on the PLLP structure, normal functions, and role in diseases.
... The genomic profiling differences between PBC and BCBM have been analyzed in several studies. Priedigkeit [140]. ...
Simple Summary
In this review, we present the latest information on the pathophysiology, diagnosis, and local and systemic treatment of brain metastases from breast cancer, with a focus on recent publications. Improving the local treatment and subtype-specific systemic therapies through advancements in basic and translational research will contribute to better clinical outcomes for patients with breast cancer brain metastasis.
Abstract
Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood–brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials.
... RNA sequencing analysis has revealed that SLC7A11 is upregulated in brain metastatic breast cancer tissues, implying a role for SLC7A11 in breast cancer metastasis [314]. In 2017, Ge et al. reported that downregulation of SLC7A11 could confer adriamycin resistance to MCF-7 breast cancer cells by over-expressing P-gp-mediated increased ROS level [315]. ...
Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.
... xCT (the heterodimer of SLC7A11 and SLC3A2) is essential for maintaining the redox balance of cells and the increased expression of xCT in cancer cells allows cells to reduce their oxidative stress and avoid apoptosis [158,200]. This dimer has upregulated expression in breast cancers that metastasize and inhibition of SLC7A11 (the functional subunit of xCT) delays lung metastasis, suggesting that xCT plays a significant role in cancer metastasis [202,203]. SLC43A1, similarly to LAT1, has upregulated expression in cancers as a source of essential amino acids (in particular leucine) [191,204]. SLC43A1 has also been implicated in cell proliferation and is particularly implicated in the severity of prostate cancers [194]. ...
This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.
