CD68 positive and/or CD163 positive tumor-associated macrophages and PD-L1 expression in breast phyllodes tumor.

INTRODUCTION: PD-L1 expression and tumor-associated macrophage (TAM) status in phyllodes tumors (PT) have only been examined in a limited number of studies. This study aimed to investigate the expression of PD-L1 and TAM in breast PT and examine their implications. METHODS: Tissue microarrays were constructed from 181 PT samples, and immunohistochemistry for PD-L1 antibodies (SP142, SP263, and 22C3) and TAM markers (CD68 and CD163) were performed. The staining results were compared and analyzed with clinicopathological parameters. RESULTS: Of the 181 samples, 149 were benign, 27 were borderline, and five were malignant. The number of CD68- and/or CD163-positive TAMs increased with increasing PT grades (P < 0.001), and the number of CD68-positive TAMs was significantly positively correlated with that of CD163-positive TAMs (R = 0.704, P < 0.001). Some of the CD68- and/or CD163-positive cells exhibited positivity for actin staining, displaying hybrid characteristics that resemble both histiocytes and myofibroblasts. PD-L1 SP263 tumor cells and PD-L1 SP263 immune cells were the most expressed in malignant PTs (P < 0.001). The number of CD68- and/or CD163-positive TAMs increased when PD-L1 SP263 immune cells were expressed (P < 0.001). The number of CD68- and/or CD163-positive TAMs was positively correlated with PD-L1 22C3 immune cells (R = 0.299, P < 0.001 and R = 0.336, P < 0.001, respectively). Univariate analysis showed that PD-L1 SP263 immune cell expression (P = 0.016) was associated with shorter disease-free survival and that PD-L1 22C3 tumor cell expression (P < 0.001) was associated with shorter overall survival. CONCLUSION: The number of CD68- and/or CD163-positive cells increases with increasing PT histological grade, and these cells exhibit hybrid characteristics, resembling both histiocyte and myofibroblasts.

Programmed death-ligand 1 expression in carcinoma of unknown primary.

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.

Expression of EMP 1, 2, and 3 in Adrenal Cortical Neoplasm and Pheochromocytoma.

The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader implications of this. Tissue microarrays were constructed for 132 cases of adrenal cortical neoplasms (ACN) (adrenal cortical adenoma (115 cases), and carcinoma (17 cases)) and 189 cases of pheochromocytoma. Immunohistochemical staining was performed to identify EMP 1, 2, and 3, and was compared with clinicopathological parameters. The H-score of EMP 3 (p < 0.001) was higher in pheochromocytoma when compared to that of ACN, and the H-score of EMP 1 (p < 0.001) and EMP 3 (p < 0.001) was higher in adrenal cortical carcinomas when compared to that of adrenal cortical adenomas. A higher EMP 1 H-score was observed in pheochromocytomas with a GAPP score ≥3 (p = 0.018). In univariate analysis, high levels of EMP 1 and EMP 3 expression in ACN were associated with shorter overall survival (p = 0.001). Differences were observed in the expression of EMPs between ACN and pheochromocytoma. EMPs are associated with malignant tumor biology in adrenal cortical neoplasm and pheochromocytoma, suggesting the role of a prognostic and/or predictive factor for EMPs in adrenal tumor.

Impact of intratumoral heterogeneity on the metabolic profiling of breast cancer tissue using high-resolution magic angle spinning magnetic resonance spectroscopy.

High-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) is a useful metabolic profiling technique for human tissue. However, the impact of intratumoral heterogeneity on the metabolite levels of breast cancers is not yet established. The purpose of this prospective study was to investigate whether the tumor cell fraction of core needle biopsy (CNB) specimens of breast cancers affect metabolic profiles assessed with HR-MAS MRS. From June 2015 to December 2016, 46 patients with 47 breast cancers were enrolled. HR-MAS MRS was used for the metabolic profiling of 285 CNB specimens from the 47 cancers. Multiple CNB samples (range 2-8) for the HR-MAS MRS experiment were obtained from surgical specimens under ultrasound guidance following surgical removal of the tumor. Tumor cell fraction was expressed as a percentage of the tumor cell volume relative to the total tumor volume contained in each CNB sample. Metabolite quantification levels were compared according to primary tumor characteristics using the t-test. Multivariate analyses were performed including primary tumor characteristics and tumor cell percentages as variables. Correlations between tumor cell percentage and metabolite levels in the CNB specimens were assessed according to the immunohistochemical status of the primary tumor. In univariate analysis, levels of choline-containing compounds, glutamate, glutamine, glycine, serine, and taurine were correlated with primary tumor characteristics. In multivariate analysis, most metabolite levels were not affected by tumor cell percentage. Tumor cell percentage showed poor correlation with metabolite levels in hormone receptor-positive cancer and triple-negative cancer, and poor to fair correlation with metabolite levels in HER2-positive cancer. This study showed that differences in the tumor cell fraction of CNB samples do not affect predictions on the primary cancer from which the samples are obtained.

Glucose and glutamine metabolism-related protein expression in breast ductal carcinoma in situ.

Glucose and glutamine metabolism is involved in important tumor mechanisms. Metabolism-related protein expression has been previously reported to predict tumor prognosis. We aimed to investigate glucose and glutamine metabolism-related protein expression and its implication in breast ductal carcinoma in situ (DCIS). A tissue microarray was prepared for 205 DCIS cases. Glucose and glutamine metabolism-related proteins were immunostained. Based on the results of estrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER)-2, and Ki-67, DCIS was classified into the luminal type, HER-2 type, and triple-negative breast cancer (TNBC). DCIS stroma was classified into non-inflammatory and inflammatory types per stromal histology. DCIS (N=205) was classified into luminal type (n=112), HER-2 type (n=81), and TNBC (n=12). Hexokinase II (p=0.044), GLS (p=0.003), and SLC7A5 (p<0.001) expression rates were the highest in TNBC. Inflammatory type stroma showed higher SLC7A5 (p<0.001) and SLC7A11 (p=0.008) expression rates than non-inflammatory type stroma. In summary, DCIS demonstrated differential expression of metabolism-related proteins according to the molecular subtype and stromal features. TNBC showed the highest glucose and glutamine metabolism-related protein expression, and inflammatory type stroma showed higher glutamine metabolism-related protein expression than non-inflammatory type stroma.

Cell Component and Function of Tumor Microenvironment in Thyroid Cancer.

Thyroid cancer is the most common cancer in the endocrine system. Most thyroid cancers have good prognosis, but some of them are resistant to treatment or show aggressive behavior. Like other tumors, thyroid cancers harbor tumor microenvironment (TME) composed of cancer associated fibroblasts (CAF) and immune cells. Autoimmune lymphocytic thyroiditis can occur in the thyroid, and it may be associated with cancer development. TME is involved in tumor progression through various mechanisms: (1) CAF is involved in tumor progression through cell proliferation and extracellular matrix (ECM) remodeling; and (2) immune cells are involved in tumor progression through cell proliferation, angiogenesis, epithelial mesenchymal transformation (EMT), and immune suppression. These events are activated by various cytokines, chemokines, and metabolites secreted from cells that comprise TME. This review is focused on how CAF and immune cells, two important cell components of thyroid cancer TME, are involved in tumor progression, and will explore their potential as therapeutic targets.

Mechanical cue-induced YAP instructs Skp2-dependent cell cycle exit and oncogenic signaling.

Mechanical tensions are usually generated during development at spatially defined regions within tissues. Such physical cues dictate the cellular decisions of proliferation or cell cycle arrest. Yet, the mechanisms by which mechanical stress controls the cell cycle are not yet fully understood. Here, we report that mechanical cues function upstream of Skp2 transcription in human breast cancer cells. We found that YAP, the mechano-responsive oncogenic Hippo signaling effector, directly promotes Skp2 transcription. YAP inactivation induces cell cycle exit (G0) by down-regulating Skp2, causing p21/p27 to accumulate. Both Skp2 reconstitution and p21/p27 depletion can rescue the observed defect in cell cycle progression. In the context of a tissue-mimicking 3D culture system, Skp2 inactivation effectively suppresses YAP-driven oncogenesis and aberrant stiff 3D matrix-evoked epithelial tissue behaviors. Finally, we also found that the expression of Skp2 and YAP is positively correlated in breast cancer patients. Our results not only reveal the molecular mechanism by which mechanical cues induce Skp2 transcription, but also uncover a role for YAP-Skp2 oncogenic signaling in the relationship between tissue rigidity and cancer progression.

Expression of Glucose Metabolism-Related Proteins in Adrenal Neoplasms.

PURPOSE: The aim of this study was to investigate the expression patterns of glucose metabolism-related proteins and their clinicopathologic implications in adrenal cortical neoplasms (ACN) and pheochromocytoma (PCC). METHODS: Immunohistochemical staining was performed to evaluate glucose metabolism-related proteins (GLUT1, CAIX, hexokinase II, G6PDH, PHGDH, and SHMT1) in 132 ACN cases (115 adrenal cortical adenoma [ACA] and 17 adrenal cortical carcinoma [ACC]) and 189 PCC cases. RESULTS: Expression levels of GLUT1 in tumor cells ([T]; p < 0.001), GLUT1 in stromal cells ([S]; p < 0.001), G6PDH (p < 0.001), and SHMT1 (p = 0.002) were higher in ACN than in PCC. GLUT1 (T; p = 0.045) and PHGDH (p = 0.043) levels were higher in ACC than in ACA. In a univariate analysis of ACN, GLUT1 (T; p = 0.017), CAIX (S; p = 0.003), and PHGDH (p = 0.009) levels were correlated with a shorter overall survival (OS). GLUT1 (T; p = 0.001) and PHGDH (p < 0.001) were related to a shorter OS in PCC. GLUT1 (T) positivity (p = 0.043) in ACN predicted a poor OS in a multivariate Cox analysis. In PCC, high GAPP score (p = 0.026), GLUT1 (T; p = 0.002), and PHGDH (p < 0.001) were independent prognostic factors for poor OS. CONCLUSIONS: The adrenal gland tumors ACN and PCC had different expression patterns of glucose metabolism-related proteins (GLUT1, G6PDH, and SHMT1), with higher expression levels in ACN than in PCC. GLUT1 and PHGDH were significant prognostic factors in these adrenal neoplasms.

Autophagy-Related Proteins Are Differentially Expressed in Adrenal Cortical Tumor/Pheochromocytoma and Associated with Patient Prognosis.

The aim of this research was to evaluate the expression and concomitant implications of LC3A, LC3B, beclin-1, and p62, which are key components of autophagy in human adrenal gland tumors. Tissue microarray was made for 321 cases of adrenal gland tumor (adrenal cortical adenoma (ACA): 115, adrenal cortical carcinoma (ACC): 17, and pheochromocytoma (PCC): 189). Immunohistochemical staining was performed for beclin-1, p62, LC3A, and LC3B, and the results were compared with the patients' clinicopathologic parameters. LC3A, LC3B, beclin-1, and LC3B isolated single positive cells (ISPC) positivity rates were higher in PCC than in adrenal cortical tumor (ACT), whereas p62 positivity was lower in PCC than in ACT. The proportion of positive LC3B (ISPC) was higher in ACC than in ACA. In addition, the proportion of cells positive for p62 and LC3B (ISPC) was significantly higher in PCCs with a GAPP score of ≥3. In univariate Cox analysis, p62 positivity (p = 0.014) and the presence of p62 (ISPC) (p = 0.001) were associated with shorter disease-free survival in PCC. Moreover, p62 positivity was predictive of shorter overall survival (OS) in patients with PCC by multivariate analysis (relative risk, 6.240; 95% CI, 1.434-27.15; p = 0.015). Differences were found in the expression of autophagy-related proteins according to adrenal gland tumor types. Compared to ACT, the proportion of LC3A, LC3B, beclin-1, and LC3B (ISPC) positivity was higher in PCC, whereas p62 positivity was lower. Similarly, p62 positivity in PCC was associated with patient prognosis of OS.

Factors Predicting Breast Cancer Development in Women During Surveillance After Surgery for Atypical Ductal Hyperplasia of the Breast: Analysis of Clinical, Radiologic, and Histopathologic Features.

BACKGROUND: This study aimed to evaluate the risk of breast cancer development for women under surveillance after surgery for atypical ductal hyperplasia (ADH), as well as the clinical and pathologic factors associated with breast cancer development. METHODS: From November 2003 to December 2014, the study included 205 women (mean age, 47.1 ± 11.2 years; range 18-73 years) with a pathologic diagnosis of ADH at surgical excision who had preoperative mammography and ultrasonography (US) images and pathology slides available for review. The patients were classified into three groups according to the detection method as follows: negative group (with ADH occult on imaging), mammography group (with ADH detected on mammography), and US group (with ADH detected on US only). Clinical, radiologic, and histopathologic factors associated with breast cancer development after ADH surgery were evaluated. RESULTS: Breast cancer developed in 15 patients (7.3%) during surveillance after ADH surgery (follow-up period, 63.9 ± 40.8 months). Palpable lesions had significantly higher rates of breast cancer development after ADH surgery (26.7% vs 6.8%; P = 0.045). Breast cancer development after ADH surgery did not differ according to the detection method (P = 0.654). Palpability was significantly associated with breast cancer development during surveillance after ADH surgery (hazard ratio, 3.579; 95% confidence interval 1.048-12.220; P = 0.042). CONCLUSION: The breast cancer development rate for women under surveillance after ADH surgery was 7.3%. Palpability at the time of ADH diagnosis was significantly associated with breast cancer development.

The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis.

The morbidity and mortality of breast cancer is mostly due to a distant metastasis, especially to the bone. Many factors may be responsible for bone metastasis in breast cancer, but interactions between tumor cells and other surrounding types of cells, and cytokines secreted by both, are expected to play the most important role. Bone marrow adipocyte (BMA) is one of the cell types comprising the bone, and adipokine is one of the cytokines secreted by both breast cancer cells and BMAs. These BMAs and adipokines are known to be responsible for cancer progression, and this review is focused on how BMAs and adipokines work in the process of breast cancer bone metastasis. Their potential as suppressive targets for bone metastasis is also explored in this review.

Clinicopathologic Characteristics of Breast Cancer According to the Infiltrating Immune Cell Subtypes.

The clinical significance of immune cell subtypes in breast cancer remains poorly understood. To identify tumor-infiltrating immune cell subtypes in breast cancer and investigate their implications, tissue microarrays were constructed using 334 cases of invasive ductal carcinoma (luminal A type: 162 (48.5%), luminal B type: 96 (28.7%), HER-2 type: 21 (6.3%), and triple negative breast cancer: 55 (16.5%)). Hormone receptors (ER, PR, and HER-2), Ki-67, and immune cell subtype-related proteins (STAT4, STAT6, FOXP3, CD8, CD68, and CD163) were assessed immunohistochemically. The proportion of highly expressed STAT6, FOXP3, CD8, CD68, and CD163 proteins was found to be lowest in luminal A type but highest in the HER-2 type. Additionally, high-level STAT6, FOXP3, CD68, and CD163 protein expression was associated with higher histologic grade. ER negativity was associated with high STAT6, FOXP3, and CD163 expression levels, whereas PR negativity and high Ki-67 labeling index were associated with high CD163 expression. Univariate (p = 0.003) and multivariate Cox (hazard ratio: 2.435, 95% CI: 1.110-5.344, p = 0.049) analyses showed that high CD8 expression is an independent factor associated with shorter disease-free survival. Immune cell subtype-related protein expression is dependent on breast cancer molecular subtypes, and CD8 expression is associated with patient prognosis.

Expression of proteins related to autotaxin-lysophosphatidate signaling in thyroid tumors.

BACKGROUND: We aimed to investigate the expression of proteins related with autotaxin (ATX)-lysophosphatidate (LPA) signaling and the clinical implications in primary and metastatic thyroid tumors. METHODS: We constructed tissue microarrays with 545 primary thyroid tumors [338 papillary thyroid carcinoma (PTC), 111 follicular carcinoma (FC), 69 medullary carcinoma (MC), 23 poorly differentiated carcinoma (PDC), and four anaplastic carcinoma (AC)]. Immunohistochemical stains for proteins related to ATX-LPA signaling (e.g., ATX, LPA1, LPA2, and LPA3) were performed. RESULTS: The expression of ATX was highest in MC, while the LPA1 expression was higher in PDC and AC, and the expression of LPA2 and LPA3 was highest in PTC (p < 0.001). Additionally, the expression of ATX, LPA1, and LPA2 was higher in conventional-type PTC than in follicular-variant PTC (p < 0.05). PTC with BRAF V600E mutation showed higher expression of ATX, LPA1, LPA2, and LPA3 than PTC without BRAF V600E mutation (p < 0.001). In univariate analysis, ATX positivity (p = 0.005) and LPA1 positivity (p = 0.014) were correlated with shorter overall survival in PTC. CONCLUSION: Proteins related to the ATX-LPA axis showed different levels of expression in primary thyroid tumors according to subtype.

Expression of Autotaxin⁻Lysophosphatidate Signaling-Related Proteins in Breast Cancer with Adipose Stroma.

This research aimed to evaluate the expression and clinical implication of autotaxin (ATX)-lysophosphatidate (LPA) signaling-related proteins in breast cancer with adipose stroma. To this end, a tissue microarray (TMA) was constructed from 137 breast cancer tissues with adipose stroma and 329 breast cancer tissues with non-adipose stroma (inflammatory stroma: n = 81, 24.6%; fibrous stroma: n = 246, 75.4%). Immunohistochemical staining for ATX-LPA signaling-related proteins (ATX, LPA1, LPA2, and LPA3) was performed on the TMA. The results showed that LPA2 in tumor cells and LPA3 in stromal cells were highly expressed in breast cancer with adipose stroma and breast cancer with adipose and inflammatory stroma, respectively. Stromal LPA1 positivity (p = 0.017) and stromal LPA3 positivity (p = 0.004) were higher in breast cancer with adipose stroma containing CD68-positive crown-like structures (CLS). Stromal ATX positivity (p = 0.010) and stromal LPA3 positivity (p = 0.009) were higher in breast cancer with adipose tissue containing CD163-positive CLS. In breast cancer with adipose stroma, the number of CD163-positive macrophages was greater with stromal ATX positivity (p = 0.003), and the number of CD68-positive and CD163-positive macrophages were greater in cases with stromal LPA3 positivity. In conclusion, ATX-LPA signaling-related proteins are highly expressed in breast cancer with adipose stroma, with associated macrophage infiltration.

Tumor-associated macrophages and crown-like structures in adipose tissue in breast cancer.

PURPOSE: We aimed to evaluate macrophage infiltration and to identify the status of crown-like structures (CLSs) in mammary adipose tissue of human breast tissue in cases with and without breast cancer. METHODS: Breast adipose tissue was obtained from reduction mammoplasty (N = 56, Group 1), non-neoplastic breast tissue of breast cancer patients (N = 84, Group 2), and breast cancer with adipose stroma (N = 140, Group 3). Immunohistochemical staining of CD68 and CD163 was performed, and the infiltrating macrophages and CLSs within breast adipose tissue were evaluated. RESULTS: Group 3 had the largest number of CD68-positive (CD68+) and CD163-positive (CD163+) macrophages and CLSs within adipose tissue (P < 0.001). Among Group 3, cases with high levels of CD68+ and CD163+ macrophages commonly had a higher histologic grade (P = 0.016 and P = 0.045), and cases with CD163+ CLSs were correlated with old age (P = 0.042), estrogen receptor negativity (P = 0.013), human epidermal growth factor receptor-2 positivity (P = 0.043), and non-luminal A type (P = 0.039). Upon univariate analysis, high levels of CD163+ macrophages were associated with shorter disease-free survival in node-negative breast cancer patients (P = 0.033), and CD68+ CLSs were associated with shorter overall survival in node-positive breast cancer patients (P = 0.015). CONCLUSIONS: CD68+ and/or CD163+ tumor-associated macrophage infiltration as well as CLSs are present in adipose tissue nearby the breast cancer lesion, and are associated with various clinicopathologic parameters of breast cancer.

Site-specific expression of amine oxidases in breast cancer metastases.

We aimed to evaluate the expression of amine oxidase-related proteins in metastatic breast cancer tissue and determine its clinical implication. A tissue microarray was constructed from a total of 126 metastatic breast tumors (31 bone metastases (24.6%), 36 brain metastases (28.6%), 11 liver metastases (8.7%), and 48 lung metastases (38.1%)). Immunohistochemical staining for amine oxidase-related proteins (lysyl oxidase, diamine oxidase, and monoamine oxidase A and B) was performed. In metastatic breast cancer tissue, lysyl oxidase ( p = 0.001), tumoral diamine oxidase ( p = 0.003), stromal diamine oxidase ( p = 0.047), and stromal monoamine oxidase B ( p = 0.002) were differentially expressed in different metastatic sites. Bone metastases showed low expression of lysyl oxidase, tumoral diamine oxidase, and stromal diamine oxidase. We observed high expression of lysyl oxidase in brain metastases, tumoral diamine oxidase in liver metastases, stromal diamine oxidase in lung metastases, and stromal monoamine oxidase B in bone metastases. Lysyl oxidase positivity was associated with progesterone receptor negativity ( p = 0.001), and monoamine oxidase A positivity was associated with human epidermal growth factor receptor-2 negativity ( p = 0.003) and the luminal A subtype ( p = 0.003). On univariate analysis shorter overall survival was associated with stromal diamine oxidase negativity ( p = 0.008), especially in lung metastases ( p = 0.025), and stromal monoamine oxidase B positivity ( p < 0.001). Stromal monoamine oxidase B positivity was an independent prognostic factor for shorter overall survival in multivariate Cox analysis (hazard ratio, 4.069; 95% confidence interval, 1.649-10.04; p = 0.002). Finally, in metastatic breast cancer, amine oxidase-related proteins were differentially expressed in a manner specific to metastatic site, and stromal monoamine oxidase B expression was correlated with prognosis.

Differential Expression of Cancer-Associated Fibroblast-Related Proteins in Ductal Carcinoma in situ According to Molecular Subtype and Stromal Histology.

OBJECTIVE: The purpose of this study is to investigate the expression of cancer-associated fibroblast (CAF)-related proteins and their implication in ductal carcinoma in situ (DCIS). METHODS: We constructed a tissue microarray of 223 cases of DCIS and examined immunohistochemical staining for the 7 CAF-related proteins. We classified DCIS into luminal type, human epidermal growth factor receptor-2 (HER-2) type, and triple negative breast cancer (TNBC) according to the immunohistochemical results for estrogen receptor, progesterone receptor, and HER-2. We also classified DCIS into desmoplastic, normal-like, and inflammatory type according to stromal histology. RESULTS: There were significant differences in the expression of S100A4, podoplanin, prolyl 4-hydroxylase subunit alpha 3, NG2, and PDGFRα in stromal cells of DCIS when classified according to molecular subtype. The expression rate of all CAF-related proteins in stromal cells was higher in the HER-2 type and TNBC than in the luminal type (p < 0.001). When classified according to stromal subtype, there were significant differences in the expression of all CAF-related proteins in stromal cells, with the inflammatory stromal type showing higher expression of CAF-related proteins than other stromal types. CONCLUSION: The expression of CAF-related proteins in stromal cells of DCIS varies according to molecular subtype and stromal type.

Amino Acid Transporters and Glutamine Metabolism in Breast Cancer.

Amino acid transporters are membrane transport proteins, most of which are members of the solute carrier families. Amino acids are essential for the survival of all types of cells, including tumor cells, which have an increased demand for nutrients to facilitate proliferation and cancer progression. Breast cancer is the most common malignancy in women worldwide and is still associated with high mortality rates, despite improved treatment strategies. Recent studies have demonstrated that the amino acid metabolic pathway is altered in breast cancer and that amino acid transporters affect tumor growth and progression. In breast cancer, glutamine is one of the key nutrients, and glutamine metabolism is closely related to the amino acid transporters. In this review, we focus on amino acid transporters and their roles in breast cancer. We also highlight the different subsets of upregulated amino acid transporters in breast cancer and discuss their potential applications as treatment targets, cancer imaging tracers, and drug delivery components. Glutamine metabolism as well as its regulation and therapeutic implication in breast cancer are also discussed.

Glycolysis-related protein expression in thyroid cancer.

We aimed to demonstrate the differences in the expression of glucose metabolism-related proteins according to the thyroid cancer subtypes and investigate the implications of these differences. A total of 566 thyroid cancer patients, including 342 cases of papillary thyroid carcinoma, 112 cases of follicular carcinoma, 70 cases of medullary carcinoma, 23 cases of poorly differentiated carcinoma, 19 cases of anaplastic carcinoma, and 152 cases of follicular adenoma, were enrolled in the study. Immunohistochemical staining for glucose transporter 1, hexokinase II, carbonic anhydrase IX, and monocarbonylate transporter 4 was performed, and the relationship between immunoreactivity and clinicopathologic parameters was analyzed. Glucose transporter 1 and tumoral monocarbonylate transporter 4 expression levels were shown to be the highest in anaplastic carcinoma, and medullary carcinoma showed the highest carbonic anhydrase IX and lowest hexokinase II levels compared with other subtypes. Stromal expression of monocarbonylate transporter 4 was observed in papillary thyroid carcinoma and anaplastic carcinoma samples. Conventional papillary thyroid carcinoma tumors expressed higher levels of glucose transporter 1, and tumoral and stromal monocarbonylate transporter 4, than the follicular variant, which showed a higher expression of carbonic anhydrase IX. Papillary thyroid carcinoma samples with BRAF V600E mutation were shown to have higher glucose transporter 1, hexokinase II, carbonic anhydrase IX, and tumoral monocarbonylate transporter 4 expression levels. Univariate analysis showed that papillary thyroid carcinoma cases with glucose transporter 1 positivity had shorter overall survival, patients with medullary carcinoma and hexokinase II positivity were shown to have a shorter disease-free survival and overall survival, and tumoral monocarbonylate transporter 4 positivity was associated with shorter overall survival compared with papillary thyroid carcinoma patients with negativity for each marker. Disease-free survival and overall survival of patients with poorly differentiated carcinoma were shown to be significantly decreased when glucose transporter 1 and tumoral monocarbonylate transporter 4 are expressed. We demonstrated that the expression levels of glycolysis-related proteins differ between thyroid cancer subtypes and are correlated with poorer prognosis, depending on the subtype.

Clinicopathological and prognostic significance of programmed death ligand-1 expression in breast cancer: a meta-analysis.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) may be a useful molecule for targeted immunotherapy. Therefore, this meta-analysis aimed to investigate PD-L1 expression in breast cancer and its associations with clinicopathological factors and outcomes, which may help determine whether PD-L1 expression is a useful prognostic marker. METHODS: The Medline Ovid, Cochrane, PubMed, Google Scholar, and Web of Knowledge databases were searched for studies that evaluated the prognostic or clinicopathological significance of PD-L1 expression in patients with breast cancer, and reported at least one survival-related outcome. RESULTS: Six studies that included 7877 cases were selected for the analysis. Higher PD-L1 expression in all cells was related to higher histological grade and lymph node metastasis. Higher PD-L1 expression in tumor cell was related to larger tumor size, estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor type-2 positivity, and triple-negative breast cancer. PD-L1 positivity in all cells was associated with poorer disease-free survival, although it was not significantly associated with overall survival. CONCLUSION: The present meta-analysis revealed that cases of breast cancer with PD-L1 positivity in all cells exhibited higher histological grades, lymph node metastasis, and poorer disease-free survival. Therefore, positive expression of PD-L1 may be a useful prognostic marker in breast cancer.