Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of ...cancer progression. Although some important roles of intracellular S1P have recently been uncovered, the majority of its biological effects are known to be mediated via activation of five specific G protein-coupled receptors S1P receptor (S1PR)1–S1PR5 located on the cell surface. Secretion of S1P produced inside cells by sphingosine kinases can then signal through these receptors in autocrine, paracrine, and/or endocrine manners, coined “inside-out” signaling of S1P. Numerous studies suggest that secreted S1P plays important roles in cancer progression; thus, understanding the mechanism by which S1P is exported out of cells, particularly cancer cells, is both interesting and important. Here we will review the current understanding of the transport of S1P out of cancer cells and its potential roles in the tumor microenvironment.
The tumor microenvironment (TME) plays a crucial role in tumor progression, therapeutic response, and patient outcomes. TME includes immune cells, blood and lymphatic vessels, and so on. There are ...anti-cancer and pro-cancer immune cells. In general, infiltration of anti-cancer immune cells, such as cytotoxic T cells (CTLs), is associated with a favorable patient prognosis. In contrast, infiltration of pro-cancer immune cells, such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), is associated with a worse prognosis. However, some immune cells, which play an ambivalent role in cancer immunity, have demonstrated contradictory impacts on patient prognosis. Blood and lymphatic vessels play crucial roles in TME not only as delivery and draining systems of fluid and molecules, but also allowing cancer cells access to systematic circulation to metastasize. Angiogenesis promotes cancer aggressiveness and is associated with a worse prognosis. Its targeted therapy shows a benefit in some cancers, however, because the target can vary by caner type, a benefit of anti-angiogenesis therapy is limited in the current standard of care. Lymphangiogenesis plays a role in lymph node metastasis, thus, it is associated with a poor prognosis in some cancers. To study TME, the mouse model is one of the most commonly used tools. The choice of appropriate mouse model depends on the hypothesis being tested and the scientific question being asked. Here, we review recent studies that investigated the clinical relevance of TME components and introduce mouse models to study TME.
is one of the most studied oncogenes that is known to promote cell proliferation. We utilized MYC targets v1 and MYC targets v2 scores of gene set variation analysis and hypothesized that these ...scores correlate with tumor aggressiveness and survival outcomes. We examined a total of 3109 breast cancer patients from TCGA, METABRIC, and GSE124647 cohorts. In each cohort, the patients were divided into high- and low-score groups using the upper third value as the cut off. As expected, higher scores were related to increased cell proliferation and worse clinical and pathologic features. High MYC targets scores were associated with worse survival, specifically in primary ER-positive breast cancer, consistently in both TCGA and METABRIC cohorts. In ER-positive breast cancer, high MYC targets v1, but not v2 score, was associated with high mutation load, and high MYC targets v1 and v2 scores were both associated with increased infiltration of pro- and anti-cancerous immune cells. We found that high MYC scores were associated with worse survival in metastatic breast cancer. Our findings show that the MYC targets v1 and v2 scores are associated with tumor aggressiveness and poor prognosis in ER-positive primary tumors, as well as in metastatic breast cancer.
Many inflammatory mediators are involved in the process of carcinogenesis and cancer progression. In addition to cytokines and chemokines, lipid mediators have recently attracted attention as ...signaling molecules associated with inflammatory diseases. Sphingosine‐1‐phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival and migration, immune cell recruitment, angiogenesis and lymphangiogenesis. S1P also plays a significant role in inflammation and cancer. The gradation of S1P concentration in the blood, lymph and tissue regulates lymphocyte trafficking, an important component of inflammation. Furthermore, cancer cells produce elevated levels of S1P, contributing to the tumor microenvironment and linking cancer and inflammation. Future technological advances may reveal greater detail about the mechanisms of S1P regulation in the tumor microenvironment and the contribution of S1P to cancer progression. Considering the critical role of S1P in linking inflammation and cancer, it is possible that the S1P signaling pathway could be a novel therapeutic target for cancers with chronic inflammation.
Sphingosine‐1‐phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival and migration, immune cell recruitment, angiogenesis and lymphangiogenesis. Cancer cells produce elevated levels of S1P, contributing to the tumor microenvironment and linking cancer and inflammation. Considering the critical role of S1P in linking inflammation and cancer, it is possible that the S1P signaling pathway could be a novel therapeutic target for cancers with chronic inflammation.
Background
Mutations of
BRCA
genes are the most studied in breast cancer, but the clinical relevance of
BRCA2
gene expression has been less well studied. Given that
BRCA2
is a DNA repair gene, we ...hypothesized that high
BRCA2
expression is associated with highly proliferative and aggressive biology in breast cancer.
Materials and Methods
A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA,
n
= 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (
n
= 3273) as a validation cohort.
Results
There was no relationship between
BRCA2
mutation and
BRCA2
gene expression.
BRCA2
high expression breast cancer was associated with higher Nottingham grade (
p
< 0.001), with high proliferation (MKI-67,
p
< 0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all
p
< 0.001).
BRCA2
high expression was associated with
E2F1
,
RB1
,
PALB2
, and
PARP
, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells.
BRCA2
high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC.
Conclusions
BRCA2
high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients.
BRCA2
gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.
Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS‐based gene panel ...tests has generated practical diagnostic tools that enable individualized cancer‐patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double‐strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS‐based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
The incorporation of clinically relevant target sequences into next generation sequencing (NGS)‐based gene panel tests has generated practical diagnostic tools that enable individualized cancer‐patient care. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS‐based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less ...common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRNA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs.
Background
Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T ...cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity.
Methods
Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition.
Results
High CYT was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+T cells, gamma-delta T cells, and M1 macrophages. CYT-high CRC patients had improved overall survival (
p
= 0.019) and disease-free survival (
p
= 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability, and TIL positivity. The levels of immune checkpoint molecules (ICMs)—programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)—correlated significantly with CYT (
p
< 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients.
Conclusions
High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.
CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we ...estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of
genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (
)-α and
-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy.
Pancreatic ductal adenocarcinoma (PDAC) is known for its hypovascularity. Bevacizumab, an anti-angiogenic drug, added to standard chemotherapy demonstrated no improvement in outcome for PDAC. ...Therefore, we hypothesized that increased vascularity may be associated with improved outcomes in PDAC possibly due to better delivery of tumor specific immune cells. To test this hypothesis, PDAC patients were classified into either high or low CD31 expression groups utilizing mRNA expression from RNA-sequence data in The Cancer Genome Atlas (TCGA) pancreatic cancer cohort. High expression of CD31, which indicates presence of more vascular endothelial cells, was associated with significantly better OS (p = 0.002). Multivariate analysis demonstrated that residual tumor (R1, 2; p = 0.026) and CD31 low expression (p = 0.007) were the only independent predictors that negatively impacted OS. Vascular stability as well as immune response related pathways were significantly upregulated in the CD31 high expressing tumors. Furthermore, there were higher proportions of anti-cancer immune cells infiltration, including activated memory CD4+ T cells (p = 0.038), CD8+ T cells (p = 0.027), gamma-delta T cells (p < 0.001) as well as naïve B cells (p = 0.006), whereas lower proportions of regulatory T cell fractions (p = 0.009), which induce an immune tolerant microenvironment, in the CD31 high expressing tumors. These findings imply that stable vessels supply anti-cancer immune cells, which are at least partially responsible for better OS in the CD31 high expressing tumors. In conclusion, CD31 high expressing PDACs have better OS, which may be due to stable vessels that supply anti-cancer immune cells.
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