Hirokuni Ikeda

The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells

IntroductionMicrotubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.MethodsThe correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.ResultsmRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-β-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.ConclusionsExpression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.

Overexpression of UbcH10 alternates the cell cycle profile and accelerate the tumor proliferation in colon cancer

BackgroundUbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. To assess the potential role of UbcH10 in colon cancer progression, we analyzed the clinicopathological relevance of UbcH10 in colon cancer.MethodsWe firstly screened the expression profile of UbcH10 in various types of cancer tissues as well as cell lines. Thereafter, using the colon cancer cells line, we manipulated the expression of UbcH10 and evaluated the cell cycle profile and cellular proliferations. Furthermore, the clinicopathological significance of UbcH10 was immunohistologically evaluated in patients with colon cancer. Statistical analysis was performed using the students t-test and Chi-square test.ResultsUsing the colon cancer cells, depletion of UbcH10 resulted in suppression of cellular growth whereas overexpression of UbcH10 promoted the cellular growth and oncogenic cellular growth. Mitotic population was markedly alternated by the manipulation of UbcH10 expression. Immunohistochemical analysis indicated that UbcH10 was significantly higher in colon cancer tissue compared with normal colon epithelia. Furthermore, the clinicopathological evaluation revealed that UbcH10 was associated with high-grade histological tumors.ConclusionThe results show the clinicopathological significance of UbcH10 in the progression of colon cancer. Thus UbcH10 may act as a novel biomarker in patients with colon cancer.

Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer

Patients with estrogen receptor (ER)‐positive breast cancers have a better prognosis than those with ER‐negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER‐positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5‐fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4‐hydroxytamoxifen) were examined in ER‐positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance‐associated protein 1, and microtubule‐associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4‐Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5‐fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule‐associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo. (Cancer Sci 2011; 102: 2038–2042)

Clinicopathological relevance of UbcH10 in breast cancer

Abrogated mitotic progression is a common hallmark of cancer. UbcH10, one of the components of the ubiquitin/proteasome pathway, plays a pivotal role in the regulation of mitotic progression. Abnormal UbcH10 activity is reported in certain types of human cancers; its overexpression is occasionally encountered in cancerous tissue compared with adjacent normal tissue. Current studies have suggested the critical role of UbcH10 in the spindle assembly checkpoint and the subsequent accurate separation of sister chromatids, which is orchestrated by a series of molecular interactions governed by the complex and diverse cell cycle machinery. To validate the potential role of UbcH10 in cell proliferation in cancer, we have analyzed the clinicopathological relevance of UbcH10 in progression of breast cancer using a combinatorial approach of human tumor arrays and biochemical analyses. Our results show that the percentage of tested samples which stained positive for UbcH10 in breast cancer tissues is significantly higher compared to the adjacent nonmalignant tissue. Furthermore, results from the clinicopathological analysis have revealed that elevated expression of UbcH10 is associated with higher histological grade tumors. In addition, depletion of UbcH10 by RNA interference in breast cancer cells resulted in decreased cellular proliferation, while overexpression of UbcH10 significantly enhanced cellular growth in breast cancer. Our results suggest a pathological correlation between UbcH10 and cell proliferation in breast cancer. Thus, aberrant UbcH10 activity may induce the dysfunction of proper cell cycle progression and result in the aggressive behavior of tumor cells in patients with breast cancer. (Cancer Sci 2009; 100: 238–248)

A case of a huge gastroepiploic arterial aneurysm

An 85-year-old man complaining of vague abdominal discomfort was admitted to our hospital. A pulsatile 8 × 7-cm mass in the right upper abdomen was noticed on clinical examination. Computed tomography of the abdomen showed a huge arterial aneurysm in the right gastroepiploic artery, and the left gastroepiploic artery was meandering and expanding. An image diagnosis of gastroepiploic arterial aneurysm (GEAA) was made. Because of the huge size of the aneurysm and the predicted high risk of perforation, surgical intervention was planned. The aneurysm was identified in the greater curve and was found to adhere firmly to the transverse colon. Partial resection of the stomach, aneurysmectomy and partial resection of the transverse colon were performed. Clinically, splanchnic arterial aneurysms are rare. Among them, GEAA is especially rare. We report a rare case of a huge GEAA that was treated successfully by surgery.

A case of deep femoral artery aneurysm.

A 58-year-old man presented with paralysis and pain in the left leg, and a mass was found in his thigh. Because of the growth of the mass and the worsening of his symptoms, the patient visited our hospital. Multidetector computed tomography revealed a large deep femoral arterial (DFA) aneurysm. Surgical intervention was planned because of the large size of the aneurysm, the high risk of perforation and the worsening symptoms. Aneurysmectomy and revascularization of the distal DFA with an artificial blood vessel graft were performed. DFA aneurysms are extremely rare. These aneurysms have a high rate of rupture, and surgery plays an important role in their treatment. However, standard methods have not yet been established because of their rarity of DFA aneurysm. We describe a case of DFA aneurysm in a patient who was successfully treated with aneurysmectomy and revascularization with an artificial blood vessel graft.

A case of rapidly growing osteosarcoma of the rib.

A 37-year-old woman noticed a right anterior chest mass and pain. The mass had been rapidly growing and she visited our hospital. The mass was hard and 8 × 7 cm in size. It was detected in the upper inner quadrant of her anterior chest wall. A computed tomography (CT) examination and magnetic resonance imaging (MRI) of the chest revealed a large heterogeneously enhanced mass arising from the right chest wall with lytic destruction of the rib and coarse calcification. An image diagnosis of osteogenic sarcoma originating from a rib was made. She underwent surgical excision of the tumor and chest wall reconstruction. Microscopic examination of the resected tumor showed multiple neoplastic cells accompanied by osteoid formation within the tumor. The tumor was diagnosed as high-grade malignant osteosarcoma of the rib. Primary osteosarcoma commonly originates in the long bone in children and adolescents, but it occurs very rarely in the ribs in adults. Surgical resection plays an important role in the treatment for this disease. We report a case of primary osteosarcoma that originated in the rib of a young woman and was treated successfully by surgery.

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

A patient with recurrent breast cancer showing long-term survival after developing pericardial effusion and cardiac tamponade caused by carcinomatous pericarditis.

Background: Malignant pericardial effusion caused by carcinomatous pericarditis is a complication of advanced malignancy. Breast cancer is the second most important cause of malignant pericardial effusion. Malignant pericardial effusion is the end stage of breast cancer, and the prognosis is very poor. Pericardial effusion may cause cardiac tamponade and sudden death if it is not controlled properly. There is a debate on which is the best method to control pericardial effusion. Case Report: We describe the clinical course of a 55-year-old woman with recurrent breast cancer, pericardial effusion, and cardiac tamponade caused by carcinomatous pericarditis. Thoracoscopic pericardial window was performed to control the pericardial effusion. The patient survived for about 5 years after being diagnosed with pericardial metastases. Conclusion: The observed long-term survival in such a patient with the development of pericardial effusions and cardiac tamponade caused by carcinomatous pericarditis attributable to breast cancer is rare. Thoracoscopic pericardial window was effective in controlling the pericardial effusion.

Primary closure of a spontaneous esophageal rupture under hand-assisted laparoscopy: a case report

Spontaneous rupture of the esophagus, which is also known as Boerhaave’s syndrome, is a rare life-threatening condition that requires urgent surgical management. The optimal treatment involves surgical repair of the esophageal defect, which is usually accomplished via laparotomy, thoracotomy, or both, and mediastinal debridement. Here, we report a case of spontaneous rupture of the esophagus that was treated with suturing repair and drain insertion using a hand-assisted laparoscopic approach.