High expression of SDC1 in stromal cells is associated with good prognosis in colorectal cancer.

We have previously reported that patients with high Syndecan 1 (SDC1) expression in colorectal cancer (CRC) cells have a favorable prognosis, and we also found that stromal cells showed upregulation of SDC1, but the clinical significance is unclear. The expression of SDC1 in the stroma cells was assessed by immunohistochemistry using a tissue microarray comprising representative cores from 513 CRC patients. The correlation between the expression of SDC1 in the stroma cells and the clinicopathological features of patients was analyzed. The data showed that the expression of SDC1 in the stroma cells was correlated with the degree of differentiation ( P = 0.012) and tumor location (up or down) ( P = 0.005). Also, CRCs patients with high expression of SDC1 in the stromal cells have a good prognosis ( P = 0.0369). Accumulating evidence indicates that SDC1, whether in tumor cells or stromal cells, plays a tumor-suppressor role in CRCs.

Tumor cell-secreted exosomal miR-22-3p inhibits transgelin and induces vascular abnormalization to promote tumor budding.

Tumor budding (TB) is considered a histomorphological marker of poor prognosis in patients with breast cancer (BC). Tumor vasculature is disordered and unstable in BC, which causes restricted drug delivery, hypoxia, and tumor metastasis. Traditional anti-angiogenic treatments cause extreme hypoxia, increased invasion, metastasis, and drug resistance due to blood vessel rarefaction or regression. Therefore, the application of anti-angiogenic strategies for vascular normalization in tumors is crucial to improve therapeutic efficacy in BC. In the present study, we found that transgelin (TAGLN) promoted the normalization of tumor vessels by regulating the structure and function of endothelial cells, and knockout of TAGLN in tumor-bearing mice resulted in tumor vessel abnormalization, an increase in epithelial-mesenchymal transition characteristics of tumor cells, and promotion of TB. Moreover, BC cells secrete exosomal miR-22-3p that mediates tumor vessel abnormalization by inhibiting TAGLN. We demonstrated for the first time that TAGLN plays an essential role in tumor vessel normalization, and thus it impairs TB and metastasis. Additionally, the findings of this study indicate that exosomal miR-22-3p is a potential therapeutic target for BC.

miR-378d suppresses malignant phenotype of ESCC cells through AKT signaling.

BACKGROUND: Post-resistance progress in paclitaxel (PTX) treatment remains a major challenge in tumor treatment. A high dose of PTX was used for cell lines to analyze the changes in molecular expression. The miR-378d was sharply reduced in surviving cells, but the role of miR-378d in Esophageal squamous cell carcinoma (ESCC) remained unclear. METHODS: We analyzed the relationship between miR-378d expression and the clinicopathological features of ESCC. We constructed miR-378d silent expression cell lines to study phenotypes and molecular mechanisms. RESULTS: The miR-378d expression was associated with good prognosis in patients with ESCC. miR-378d inhibition promoted chemo-resistance, monoclonal formation, EMT, migration, invasion, stemness, and metastasis of ESCC cells. miR-378d can target downregulated AKT1. CONCLUSIONS: Therefore, miR-378d expression is a good prognostic factor of patients with ESCC and regulates the malignant phenotype of tumor cells through AKT.

Histopathological validation of safe margin for nephron-sparing surgery based on individual tumor growth pattern.

BACKGROUND: To evaluate the clinicopathologic value of morphological growth patterns of small renal cell carcinoma (sRCC) and determine the actual demand for taking a rim of healthy parenchyma to avoid positive SM. METHODS: Data was collected from 560 sRCC patients who underwent laparoscopic surgeries from May 2010 to October 2017. One hundred forty-nine cases received nephron-sparing surgery (NSS) and others received radical nephrectomy (RN). All specimens were analyzed separately by two uropathologists, and three morphological growth patterns were identified. The presence of pseudocapsule (PC), surgical margins (SM), and other routine variables were recorded. The relationship between growth patterns and included variables was measured by the χ2 test and Fisher's exact probability test. Survival outcomes were evaluated by Kaplan-Meier method and the log-rank test. RESULTS: The median age of patients was 63.2 years old and the mean tumor diameter was 3.0 cm. Four hundred eighty (85.7%) cases were clear cell RCC and 541 (96.6%) cases were at the pT1a stage. Peritumoral PC was detected in 512 (92.5%) specimens, and the ratio of tumor invasion in PC in infiltration pattern increased obviously than that of the other growth patterns. Similarly, the pT stage was significantly correlated with the infiltration pattern as well. One hundred forty-nine patients underwent NSS and 3 (2.0%) of them showed positive SM after operation. Statistical differences of the 5-year overall survival (OS) and the cancer-specific survival (CSS) existed between different morphological growth patterns, PC status, and pT stages. CONCLUSIONS: Morphological growth patterns of sRCC might be used as a potential biomarker to help operate NSS to avoid the risk of positive SM. How to distinguish different morphological growth patterns before operation and the effectiveness of the growth pattern as a novel proposed parameter to direct NSS in sRCC patients deserves further exploration.

Unusual subcutaneous dedifferentiated liposarcoma exhibiting coexistence of meningothelial-like whorls and inflammatory myofibroblastic tumor-like structures.

To explore the clinicopathological features of a rare dedifferentiated liposarcoma (DDLPS) with meningothelial-like whorls, we retrospectively analyzed 46 reported cases and 1 case that we encountered. Fluorescence in situ hybridization (FISH) analysis of the MDM2 amplification status of our case was also performed. Our case involved a 73-year-old male patient who had a mass in the upper part of his left arm for 10 years and was treated by surgical ablation of the tumor because of the mass' recent rapid enlargement. Microscopically, the tumor tissues showed coexistence of well-differentiated and dedifferentiated components, the latter of which included meningothelial-like whorls and inflammatory myofibroblastic tumor-like structures. The dedifferentiated components diffusely expressed vimentin, MDM2, CDK4, p16, and smooth muscle actin. They were also focally positive for desmin but negative for S-100, CD117, CD34, ALK, EMA, SOX-10, p53, and ß-catenin. FISH detection showed MDM2 amplification. In conclusion, subcutaneous DDLPS with meningothelial-like whorls and inflammatory myofibroblastic tumor-like features is rare. This case broadens the histopathological lineage of DDLPS, and confirms DDLPS with myogenic differentiation. The use of the combination of MDM2, CDK4, p16, and FISH to detect MDM2 amplification is a reliable basis for the diagnosis of DDLPS with meningothelial-like whorls.

Overexpression of dedicator of cytokinesis 2 correlates with good prognosis in colorectal cancer associated with more prominent CD8+ lymphocytes infiltration: a colorectal cancer analysis.

Recently, dedicator of cytokinesis 2 (DOCK2) has been reportedly exhibited high mutation prevalence in the Asian colorectal cancer (CRC) cohort. However, the expression pattern of DOCK2 and its clinical significance in CRC were still unknown. To characterize the role of DOCK2, a tissue microarray (TMA) containing 481 archived paraffin-embedded CRC specimens was performed by immunohistochemistry. Among which, 54 primary CRC tissues showed high expression of DOCK2 protein, while others were negative. Moreover, DOCK2 expression was positively associated with invasion depth (P < .001) and tumor size (P = .016). Significantly, Kaplan-Meier survival analysis revealed that patients with higher DOCK2 expression had a longer overall survival time (P = .017). Furthermore, univariate and multivariate Cox regression analysis confirmed that DOCK2 is an independent prognostic marker in CRC (P = .049,; HR, 0.519; 95% CI, 0.270 to 0.997). In addition, we observed a strong correlation between the infiltration of CD8+ T lymphocytes and DOCK2 expression (P = .0119). Our findings demonstrated that overexpressed DOCK2 might involve in recruiting CD8+ T lymphocytes and serve as a novel prognostic indicator and indicated a potential therapeutic strategy by restoring DOCK2 for CRC.

Vimentin is a crucial target for anti-metastasis therapy of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck cancer, with tendency to spread to regional lymph nodes and distant organs at early stage. Vimentin, a major cytoskeletal protein constituent of the intermediate filament, plays a critical role in the epithelial-mesenchymal transition. Overexpression of vimentin is considered to be a critical prerequisite for metastasis in numerous human cancers. Therefore, targeting vimentin for cancer therapy has gained a lot of interest. In the present study, we detected vimentin expression in NPC tissues and found that overexpression of vimentin is associated with poor prognosis of NPC patients. Silencing of vimentin in NPC CNE2 cells by RNAi suppresses cells migration and invasion in vitro. However, blocking vimentin did not affect cell proliferation of CNE2 cells. In addition, the in vivo metastatic potential of CNE2 cells transfected with Vimentin shRNA was suppressed in a nude mouse model of pulmonary metastasis. Silencing of Vimentin in CNE2 cells leads to a decrease of microvessel density and VEGF, CD31, MMP2, and MMP9 expressions in pulmonary metastatic tumors. Importantly, we found that it is easier for the tumor cells from the high vimentin-expressing pulmonary metastatic tumors to reinvade the microvessel and to form stable tumor plaques attached to the endothelial cells, which resemble the resource of circulating tumor cells and are very hard to eliminate. However, depletion of vimentin inhibits the formation of vascular tumor plaques. Our findings suggest that RNAi-based vimentin silencing may be a potential and promising anti-metastatic therapeutic strategy for NPC.

Pathological features of transplanted tumor established by CD133 positive TJ905 glioblastoma stem-like cells.

BACKGROUND: This study is to explore the pathological features of transplanted tumor established by CD133 positive TJ905 glioblastoma stem-like cells. METHODS: CD133 positive TJ905 glioma cells were separated by immunomagnetic beads to isolate glioma stem-like cells. TJ905 cells and stem-like cells were inoculated subcutaneously into the mice to establish model of transplanted tumor, respectively. Mice growing condition and behavior were observed. HE staining assay, immunohistochemical assay for GFAP, Ki-67 and Olig-2, and CD34 marked microvascular density (MVD) test were performed. RESULTS: The growing condition and behavior of mice in TJ905 stem cell group was more exaggerated and the models showed stronger malignant features pathologically than that in TJ905 cell group. Glial fibrillary acidic protein (GFAP) in TJ905 cell and stem-like cell group showed the transplanted tumor originated from astrocytes. Expression of Ki-67 and oligodendrocyte transcription factor-2 (Olig-2) in TJ905 stem cells was higher notably and CD34 expression in stem cell group was significantly higher than that in the other two groups. CONCLUSIONS: Pathological features of transplanted tumor established by CD133 positive glioblastoma stem-like cells show more malignant. Use of TJ905 stem cells to establish transplanted tumor model in nude mice is excellent for glioma research.

Adult metanephric adenoma presumed to be all benign? A clinical perspective.

BACKGROUND: In most documented literature, metanephric adenoma (MA) is described as a benign tumour. Nevertheless, the nature of MA remains unclear and the clinical criteria of different MA subtypes are not well established. In the present study, we investigated the clinicopathological characteristics of MA, especially those of the uncommon histological subtypes. METHODS: A cohort study was performed on 18 patients with pathologically proven MA in our institute from January 2004 to June 2014. The patients' clinicopathological and radiological data were retrospectively analysed and evaluated with an emphasis on the corresponding subtypes. RESULTS: The patient population had a female: male ratio of 1:1 and mean age of 50 years (range, 18-66 years). The mean tumour size was 3.9 cm (range, 1.4-9.0 cm). There were no pathognomonic radiological features that posed a challenge for a preoperative diagnosis of MA. Fourteen patients underwent radical nephrectomy, and the other four underwent partial nephrectomy. Three histological subtypes were observed: classic MA (n = 10), malignant MA (n = 2), and composite MA with coexistence of different malignant components (n = 6). Despite the presence of atypical histological features and malignant components among the patients, only one patient developed distant metastasis (median postoperative follow-up, 56 months; range, 30-86 months). CONCLUSIONS: MAs are a heterogeneous group of neoplasms with different biological characteristics. The correct identification of this entity and its subtypes would facilitate stratification of optimal management protocols and accurate assessment of the prognosis.

[Clinicopathologic characteristics of sporadic renal hemangioblastoma].

OBJECTIVE: To investigate the clinicopathological characteristics of sporadic renal hemangioblastoma. METHODS: Two cases of sporadic renal hemangioblastoma were studied by histological and immunohistochemical staining, along with review of the literature. RESULTS: Both cases were presented with a renal mass during annual physical examination with an age of 40 and 45 years, respectively. The lesions located in the middle portion of the kidney with a sharp tumor border. Histopathologically, the tumors were characterized by two major components: capillary and stromal cells. Immunohistochemically, the stromal cells were positive for vimentin, NSE, S-100 protein and inhibin-α, and negative for CK, HMB45, Melan A, EMA, CD56 and syn. Both tumors showed a very low level of Ki-67 labeling. The endothelial cells were positive for CD34. CONCLUSION: Sporadic renal hemangioblastoma is a rare benign neoplasm, the diagnosis of which is based on the characteristic follicular architecture and an exclusion of other carcinomas of the kidney.

Papillary thyroid carcinoma with desmoid-type fibromatosis: the clinicopathological features with characteristic imaging and molecular correlation requiring comprehensive treatment.

The pathogenesis and treatment of papillary thyroid cancer with desmoid-type fibromatosis (PTC-DTF), a rare subtype of papillary thyroid carcinoma characterized by a mixed epithelial-mesenchymal structure, are still ill-defined. Previous reports on PTC-DTF have had limited follow-up and recurrence has been rarely reported. To better understand this condition, we conducted a thorough analysis of five cases of PTC-DTF from our institute, including clinical and pathological examinations, imaging, immunohistochemistry, and molecular analysis. We also reviewed relevant literature. The mean age of the patients was 51.8 years, with three women and two men included in the group. Ultrasound often showed a hypoechogenic and well-defined nodule in the thyroid gland, except for one individual who had distant lung metastases detected by PET-CT. The nodules ranged in width from 0.5 to 5.0 cm and were excised in each case. Following surgery, 131I therapy was used in two cases. The overall number of PTC-DTF cases has risen from the previously reported 55 to 60, with females being the most commonly affected and ranging in age from 19 to 82. Most masses underwent a thyroidectomy, and approximately half of the patients had lymph node metastases. Histologically, PTC-DTFs were composed of a predominant stromal component (65%-90%) and an intervening epithelial component. These spindle cells were arranged in parallel with abundant cytoplasm and vacuole-like nucleus but there wasn't evident atypia. The carcinoma cells were positively stained for CK and TTF-1 by immunohistochemistry, whereas mesenchymal cells were positive for SMA and displayed nuclear immunoreactivity for ß-catenin. BRAF, NRAS, and CTNNB1 mutations were identified in the epithelial and mesenchymal components through molecular testing, respectively. Perhaps because the mesenchyme harbors aberrant nuclear ß-catenin expression, PTC-DTF is more aggressive and prone to invasion and distant recurrence, as shown by our case 2, which is the first case to be reported thus far. PTC-DTF is typically treated with surgery, but clinicians may occasionally consider more holistic treatment plans that involve radioactive iodine and endocrine therapy.

Sialadenoma papilliferum: clinicopathologic, Immunohistochemical, molecular analyses of new five cases and review of the literature.

BACKGROUND: Sialadenoma papilliferum (SP) is an extremely rare benign neoplasm of salivary glands. To explore and define the clinicopathological features of SP, we retrospectively analyzed 89 cases previously reported and five new cases. METHODS: The clinical features, histopathology, immunohistochemistry and molecular analysis of our cases were further performed and the related literatures were reviewed and analyzed. RESULTS: Combining 89 cases from the literature with our cases, the hard palate was the most common locations for SP. However, two of our cases were rarely located in the esophageal mucosa. Among all cases, the male gender was more affected, with the average age and median age of 61.8 and 62 years, respectively. Conventional histomorphologically, SP was characterized by complex papillary structures with a biphasic growth pattern of exophytic squamous component and endophytic glandular component. The glandular structures were lined by a double layer of epithelium composed of flattened or cuboidal basal cells and a cuboidal or columnar luminal cells formed papillary infoldings into the ductal lumina. Immunohistochemically, the luminal epithelial configurations showed strong expression of CK7 along the luminal cell membrane, while the basal myoepithelia displayed strong nuclear p63 expression. In both the glandular and squamous tumour components showed BRAF V600E-positive immunostaining and BRAF V600E mutation. CONCLUSION: For the first time, we have comprehensively aggregated and analyzed 90 cases sialadenoma papilliferum from almost all previous publications, and further explored the clinicopathological features of SP; concordantly, this study demonstrated that SP shows a papillomatous growth pattern with exophytic and endophytic proliferation of ductal epithelium composed of double-layered cells harboring BRAF V600E mutation. Additionly, adequate treatment for SP is surgical excision, with a favorable prognosis in patients.

Sporadic hemangioblastoma of the kidney: a clinicopathologic study of three cases and a literature review.

Much attention has been paid to renal hemangioblastoma, but there are still challenges in its differential diagnosis. Three cases (2 men, 1 woman; age: 40-56 years) presented with renal tumors. The tumors were surrounded by a thick fibrous capsule, well-demarcated from the surrounding renal parenchyma, and composed of sheets or nests of polygonal to short spindle-shaped tumor cells with a rich capillary network. In cases 1 and 3, the large polygonal tumor cells contained abundant pale or eosinophilic cytoplasm, and some possessed intracytoplasmic lipid vacuoles. In case 2, tumor cells were characterized by a uniform size, mild, clear, or lightly stained cytoplasm, and typical "clear cell" appearance. Immunohistochemistry revealed that the polygonal stromal cells were strongly and diffusely positive for α-inhibin, neuron-specific enolase (NSE), S100 protein, and vimentin. Cluster of differentiation (CD)10 and paired box gene (PAX)8 were positive, while epithelial membrane antigen (EMA) and cytokeratin (CK) were focally positive in case 3. CD34 and CD31 outlined the contours and distribution of the vascular networks. Renal hemangioblastoma is rare and prone to misdiagnosis; more attention should be paid to the morphological features and reasonable application of immunohistochemistry in the diagnosis of hemangioblastoma.

Evaluation of allelic alterations in short tandem repeats in papillary thyroid cancer.

BACKGROUND: Malignant tissue samples may be the only source of biological material for forensic investigations, including individual identification or paternity testing; however, such samples may lead to uncertainties due to frequent genomic aberrations associated with tumors, including alterations of the short tandem repeat (STR) loci used for forensic casework. METHODS: Short tandem repeat loci routinely used in forensic analysis (n = 23) were analyzed in 68 surgically removed papillary thyroid cancer specimens. Tumor cells and normal stromal cells were separated by laser capture microdissection. RESULTS: Four kinds of changes were detected between normal and tumor tissues: partial loss of heterozygosity (pLOH), complete loss of heterozygosity, an additional allele, and a new allele not found in normal tissue. These changes were distributed across 20 of the tested STRs, with no mutations in VWA, D16S539, or Penta D. The most frequently affected locus was D2S1338, and the most frequent type of alteration was pLOH. Samples from patients aged 40-59 years exhibited the highest frequencies of STR variation. CONCLUSION: Our results suggest that great care should be taken in the evaluation of DNA typing results obtained from malignant tissues, particularly when no normal tissue reference samples are available.

ALDH1A1 maintains the cancer stem-like cells properties of esophageal squamous cell carcinoma by activating the AKT signal pathway and interacting with ß-catenin.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a marker of cancer stem-like cells (CSCs), but knowledge about the molecular mechanism of ALDH1A1 in maintaining the properties of CSCs remains limited. ALDH1A1 immunohistochemistry was performed in esophageal squamous cell carcinoma (ESCC) tissues, Western blotting was used to detect relationship between ALDH1A1 and AKT or ß-catenin. Subcutaneous transplantation of tumors and drug resistance, spherogenesis experiments were used to test the ESCC cell stemness. Co-IP and confocal were used to detected the co-localization of LADH1A1 and ß-catenin. ALDH1A1 expression maintained the CSC properties of ESCC cells. It enhanced the chemo-resistance ability, clonogenicity, and spherogenesis in vitro and tumorigenicity in vivo. High ALDH1A1 expression is an adverse prognostic factor of ESCC patients. Small-molecule inhibitor NCT-501 down-regulates ALDH1A1 expression and inhibits the AKT-ß-catenin signaling pathway. ALDH1A1 overexpression activates the AKT signaling pathway. ALDH1A1 interacts with ß-catenin, co-localization in KYS-510 cells.

Correction: Interaction between laminin-5γ2 and integrin ß1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins.

The original version of this Article contained an error in the author affiliations. Affiliation number 4 incorrectly read "Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Disease, Tianjin Institute of Digestive Disease". It should be "Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China".

Interaction between laminin-5γ2 and integrin ß1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins.

Colorectal cancer (CRC) is a common cancer type and a threat to human health. Tumor budding (TB) is the presence of a single cancer cell or clusters of up to five cancer cells prior to the invasive front of an aggressive carcinoma and is an independent prognosis factor for CRC. The molecular mechanism of TB is still unclear, and drugs that inhibit this process are still in the blank stage. This study found that TBs exhibit characteristics of partial EMT with a decreased expression of E-cadherin and no substantial differences in the expression of N-cadherin and vimentin. We also observed the interaction of integrin with extracellular matrix components, laminin-5γ2 (LN-5γ2), play essential roles in the TB of CRC. We then verified that the interaction between LN-5γ2 and integrin ß1 promotes the TB of CRC via the activation of FAK and Yes-associated proteins (YAP). A natural drug monomer, cucurbitacin B, was screened using virtual screening methods for the interaction interface of proteins. We found that this monomer could block the interaction interface between LN-5γ2 and integrin ß1 and substantially inhibit the TB of CRC cells via inactivation of YAP. This study provides new insights into the mechanism of TB mechanism and the development of drugs targeting the TB of CRC.