a-syngeneic-orthotopic-osteosarcoma-sprague-dawley-rat-model-with

A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate

The most recent advance in the treatment of osteosarcoma (OS) occurred in the 1980s when multi-agent chemotherapy was shown to improve overall survival ...

non-invasive-ultrasound-assessment-endometrial-cancer-progression

Non-Invasive Ultrasound Assessment of Endometrial Cancer Progression in Pax8-Directed Deletion of the Tumor Suppressors <em>Arid1a</em> and <em>Pten</em> in Mice

Uterine cancers can be studied in mice due to the ease of handling and genetic manipulation in these models. However, these studies are often limited to ...

Juntendo University Faculty of Medicine

Juntendo University School of Medicine

Cotyledonoid dissecting leiomyoma (Sternberg tumor) is a rare variant of the uterine smooth muscle tumor. Although this tumor is a benign tumor clinically and pathologically, the appearance and growth pattern is unusual, so it may be misdiagnosed as malignancy.

Cotyledonoid dissecting leiomyoma of the uterus: report of two cases.

Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial-to-mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E-cadherin- and nuclear ZEB1-positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient-derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient-matched liver metastases presumably developing through mesenchymal-to-epithelial transition. Inhibition of E-cadherin or ZEB1 expression by shRNA notably prevented the PDX-derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E-cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state.

Background. Longitudinally extensive transverse myelitis (LETM) is characterized by spinal cord inflammation extending vertically through three or more vertebral segments. The widespread use of MRI revealed LETM more frequency than ever. We report the case of a patient with pathologically confirmed small-cell lung carcinoma metastasis into the spinal cord presenting as LETM. Case Presentation. A 74-year-old man developed rapidly progressive sensorimotor disturbance and vesicorectal dysfunction. T2-weighted magnetic resonance imaging of the spine revealed LETM at the level of from T3 to conus medullaris; gadolinium enhancement showed concurrent tumor in the thoracic spinal cord from T10 to T11. Systemic survey identified a nodular mass in the lung that was verified as small-cell carcinoma. Following initial failed treatment by high-dose steroid, the patient underwent an emergent microsurgical tumor resection. Histological examination was identical with the lung carcinoma. The patient died of tumor progression at the 47th day after admission. At autopsy, only changes of edema were found in the gray matter of the cord, while tumor cells were not noted in it. Conclusion. Metastasis may rarely present symptoms of LETM. Prompt identification of underlying etiology by contrast examination and systemic survey is crucial for the patient assumed as LETM.

Longitudinally extensive transverse myelitis with intramedullary metastasis of small-cell lung carcinoma: an autopsy case report.

Overexpression of human epidermal growth factor receptor 2 (HER2) protein is well known to be more frequent in ductal carcinoma in situ (DCIS) than in invasive ductal carcinoma (IDC). However, the reasons for this difference are poorly understood. On the basis of the high frequency of estrogen receptor-positive (ER+) and HER2-positive (HER2+) DCIS, we hypothesized that this tumor type overexpresses HER2 protein without gene amplification and retrospectively investigated the HER2/neu gene status of 71 ER(+)HER2(+) DCIS, surgically removed during the 2007 to 2017 period, employing fluorescence in situ hybridization (FISH). To compare HER2 protein expressions between in situ and invasive components of individual tumors, 86 pT1mi/1a IDC with predominantly in situ disease were also examined. Furthermore, for comparison of FISH status between in situ and coexisting invasive components, another patient cohort, 78 FISH-positive IDC cases, were employed. To elucidate biological differences among DCIS with various combinations of ER and HER2 protein expressions, we also analyzed public microarray data of mRNA. HER2 gene amplification was observed in 35% of ER(+) and HER2 protein-overexpressing specimens, significantly lower than the 94% in ER-negative (ER-) and HER2 protein-overexpressing specimens (P<0.001). HER2 protein expression was decreased in the invasive component as compared with coexisting in situ portions in 40% of individual tumors, whereas the FISH status of these 2 components was well preserved. Moreover, ER(+) and HER2 protein-overexpressing DCIS showed significantly higher hypoxia-inducible factor-1α protein expression than the ER(+) and HER2 protein-nonoverexpressing tumors (P=0.016). We revealed that ER(+) and HER2 protein-overexpressing DCIS, especially ER-high tumors, frequently overexpress HER2 protein without gene amplification. Our data may provide novel insights for understanding the biology of DCIS.

Estrogen Receptor-positive Ductal Carcinoma In Situ Frequently Overexpresses HER2 Protein Without Gene Amplification.

Microsatellite instability (MSI), which reflects loss of DNA mismatch repair (MMR) activity, and immunohistochemistry (IHC) for MMR proteins are employed as screening examinations for Lynch syndrome (LS). Recent studies revealed that there is a population of MSI-high tumors in sporadic endometrial cancer (EC). However, MSI data for Japanese EC patients are scarce. Furthermore, sporadic estrogen-dependent EC (type I) is generally considered to arise from hyperplasia. Because LS is usually associated with type I EC, we hypothesized that MSI might be involved in the oncogenic process in some sporadic EC. We conducted MSI testing to reveal MSI status in sporadic Japanese EC. IHC for MMR proteins was also performed.

Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases.

Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress in A/J mice affected the development of lung tumors after postnatal response to tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to prenatal stress (PS) by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared to controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights, and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area, and aggressive morphology. Prenatal stress also induced more advanced atypical adenomatous hyperplasia (AAH) lesions. We found no difference in lung NNK-derived methyl DNA adducts, but prenatal stress did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. Prenatal stress significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. Prenatal stress did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of prenatal stress with evaluation of cancer development in offspring.

Prenatal stress enhances NNK-induced lung tumors in A/J mice.

The frequency of microsatellite instability (MSI) is reportedly extremely low in breast cancer, despite widespread clinical expectations that many patients would be responsive to immune-checkpoint inhibitors (ICI). Considering that some triple-negative breast cancers (TNBC) responded well to ICI in a clinical trial and that a high density of tumor-infiltrating lymphocytes (TILs) is frequently observed in other cancers with high levels of microsatellite instability (MSI-H), we hypothesized that some TNBC with a high density of TILs would be MSI-H. Medullary carcinoma (MedCa) of the breast, a rare histological type, is characterized by a high density of TILs. Considering that MedCa of the colon is often MSI-H, we suspected that MedCa in breast cancer might also include MSI-H tumors. Therefore, we conducted MSI tests on such breast cancers with a high density of TILs. The MSI status of 63 TIL-high TNBC and 38 MedCa tumors, all from Asian women who had undergone curative surgery, were determined retrospectively. DNA mismatch repair (MMR) proteins and PD-L1 expression were also investigated immunohistochemically. All samples were microsatellite stable, being negative for all microsatellite markers. TIL-high TNBC with low MLH1 protein had higher levels of PD-L1 in stromal immune cells (P = .041). MedCa tumors showed significantly higher PD-L1 expression in immune cells than in TIL-high TNBC (<.001). We found that MSI-H tumors were absent in TIL-high breast cancers. Examination of MMR proteins, not a purpose of Lynch syndrome screening, may merit further studies to yield predictive information for identifying patients who are likely to benefit from ICI.

Microsatellite instability and mismatch repair protein expressions in lymphocyte-predominant breast cancer.

Multi-gene expression assays have been developed with the aim of predicting late recurrence in patients with estrogen receptor (ER)-positive breast cancer. However, establishment of alternative markers based on immunohistochemistry is also important for achieving practical use. Based on our previous study, forkhead box A1 (FOXA1) protein was tested as a potentially useful predictive marker for late recurrence.

High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer.

TAFRO syndrome is a relatively new disease entity first reported in 2010. We report a case of TAFRO syndrome accommodated by abnormal exacerbation of moderately differentiated gastric adenocarcinoma. The pathophysiology of TAFRO syndrome is largely unknown, but because the disease often responds to immunosuppressive therapy and also because T follicular helper (Tfh) cells are reported to be drastically decreased in TAFRO syndrome, involvement of a dysregulated immune system can be speculated. Growing evidence points toward a pivotal role of Tfh cells in tumor immunity through supporting ectopic lymphoid structures, which are recruitment sites for cells directly engaging in antitumor activity such as CD8 T cells, NK cells, and macrophages. In fact, Tfh cells are reported to positively correlate with longer survival in human colorectal and breast cancer. Combined with our observations of hyperprogressive gastric cancer in the presented patient, an impaired tumor immunity is strongly indicated in TAFRO syndrome.

Abnormal Exacerbation of Moderately Differentiated Gastric Adenocarcinoma in a Patient with TAFRO Syndrome: An Impaired Tumor Immunity?

Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomenon, timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on  to either a control (no stress) or prenatal stress (PS) group using 2 h of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 wk from the PS group were significantly increased compared with weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macroscopic and microscopic pathology. PS groups had increased plaque thickness determined by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 wk. Five-week-old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 wk. As prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10-wk-old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared with control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further used to investigate the role of prenatal stress, telomere biology, and atherosclerosis pathogenesis in adults.

Prenatal stress enhances atherosclerosis and telomere shortening in ApoE knockout mouse offspring.

Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately.

High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs.

First Diagnosis of Immunoglobulin A Nephropathy Following SARS-CoV-2 mRNA Vaccination in Japan.

Chronic inflammation is widely recognized as a major risk factor for cancer formation, but the underlying mechanisms are poorly understood. Recently, it was shown that Gasdermin D (GSDMD) protein drives pyroptotic cell death in macrophages upon cleavage by inflammatory caspases. Even though the Gsdmd gene is specifically expressed in the intestinal epithelium, the role of Gsdmd in the intestinal tissues remains poorly characterized. In this study, we examined the biological role of Gsdmd in colorectal cancer (CRC) development, employing an azoxymethane (AOM)/dextran sulfate sodium (DSS) carcinogenesis model. Results show that Gsdmd deficiency enhances CRC development, probably due to decreased apoptosis caused by down-regulation of interferon-gamma (IFNγ) - signal transducer and activator 1 (STAT1) signaling. Furthermore, we show that GSDMD protein is diminished in human colorectal cancer, indicating involvement of GSDMD in repression of CRC development in humans. Our findings provide a new insight into functions of Gsdmd/GSDMD in colonic inflammation and human CRC development.

ArticleTotal : 2	Year
Publication title Cited by 6	2021
Publication title Cited by 1	2023

Article	Year
Cotyledonoid dissecting leiomyoma of the uterus: report of two cases. Archives of gynecology and obstetrics\| PubMed ID: 25115281	2015
Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. International journal of cancer\| PubMed ID: 31506938	2020
Longitudinally extensive transverse myelitis with intramedullary metastasis of small-cell lung carcinoma: an autopsy case report. Case reports in neurological medicine\| PubMed ID: 24455343	2013
Estrogen Receptor-positive Ductal Carcinoma In Situ Frequently Overexpresses HER2 Protein Without Gene Amplification. The American journal of surgical pathology\| PubMed ID: 31192864	2019
Usefulness of immunohistochemistry for mismatch repair protein and microsatellite instability examination in adenocarcinoma and background endometrium of sporadic endometrial cancer cases. The journal of obstetrics and gynaecology research\| PubMed ID: 31307113	2019
Prenatal stress enhances NNK-induced lung tumors in A/J mice. Carcinogenesis\| PubMed ID: 32249286	2020
Microsatellite instability and mismatch repair protein expressions in lymphocyte-predominant breast cancer. Cancer science\| PubMed ID: 32449246	2020
High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer. Breast cancer research and treatment\| PubMed ID: 32572714	2020
Abnormal Exacerbation of Moderately Differentiated Gastric Adenocarcinoma in a Patient with TAFRO Syndrome: An Impaired Tumor Immunity? Case reports in oncology\| PubMed ID: 35221963	2022
Prenatal stress enhances atherosclerosis and telomere shortening in ApoE knockout mouse offspring. American journal of physiology. Regulatory, integrative and comparative physiology\| PubMed ID: 35411811	2022
High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs. Breast cancer research : BCR\| PubMed ID: 36217150	2022
First Diagnosis of Immunoglobulin A Nephropathy Following SARS-CoV-2 mRNA Vaccination in Japan. Kidney international reports\| PubMed ID: 36277847	2023
Gasdermin D Represses Inflammation-Induced Colon Cancer Development by Regulating Apoptosis. Carcinogenesis\| PubMed ID: 36753047	2023

Harumi Saeki

Biography

JoVE Journal Publications

Other Publications