Nerve growth factor binds to the 140 kd trk proto-oncogene product and stimulates its association with the src homology domain of phospholipase C [gamma]1

The cellular actions of nerve growth factor (NGF) involve regulation of protein phosphorylation. In PC-12 pheochromocytoma cells, exposure of [125I]NGF followed by crosslinking indicates that the ligand binds to two discreet receptors, the previously described 75 kd protein, as well as the trk proto-oncogene product pp140c-trk. Competition experiments reveal that of the two, pp140c-trk binds to NGF with higher affinity. Following exposure to NGF, pp140c-trk undergoes a rapid autophosphorylation on tyrosine residues, and concomitantly phosphorylates and associates with phospholipase C[gamma]1 (PLC[gamma]1), through interaction with its src homology domains. The binding of NGF to pp140c-trk with high affinity, the NGF-dependent activation of its tyrosine kinase activity and the specific association with the effector molecule, PLC[gamma]1, suggests that this is the biologically relevant signaling receptor for NGF.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29169/1/0000215.pd

Establishment of a novel mouse xenograft model of human uterine leiomyoma

Uterine leiomyoma is the most common benign tumour in women, and an appropriate animal model for leiomyoma would be useful for exploring new therapeutic strategies. Therefore, we have been challenged to develop a new simple mouse model for human leiomyoma. Leiomyoma tissues were harvested from myomas resected by different surgical procedures with or without gonadotropin-releasing hormone agonist (GnRHa) treatment and were subcutaneously implanted into BALB/c nude mice with an estradiol/progesterone-releasing pellet. The implanted leiomyoma tissues that were obtained from the marginal site of large myomas resected by abdominal myomectomy with GnRHa treatment exhibited sufficient tumour growth in the transplanted mice. The leiomyomas that were treated with GnRHa highly expressed the estrogen/progesterone receptor genes, insulin-like growth factor 2 (IGF2) and embryonic smooth muscle myosin heavy chain (SMemb), which suggests that these factors are critical in the establishment of a mouse model of growing leiomyoma. As a result, this model will be useful for the development of new therapeutic strategies

Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

<p>Abstract</p> <p>Background</p> <p>The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα.</p> <p>Methods</p> <p>Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps.</p> <p>Results</p> <p><it>In vitro </it>study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. <it>In vitro </it>studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups.</p> <p>Conclusion</p> <p>These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.</p

Recurrent ovarian cancer presenting in the right supraclavicular lymph node with isolated metastasis: a case report

Abstract Introduction The majority of ovarian cancer recurrences are in the abdomen. However, some cases relapse as isolated lymph node metastases, mostly in pelvic or para-aortic nodes. Peripheral isolated lymph node metastasis is rare. Case presentation A 69-year-old Japanese woman had recurrent ovarian cancer presenting with isolated right supraclavicular lymph node metastasis. After surgical resection and combination chemotherapy with carboplatin and paclitaxel, her right supraclavicular lymph node completely regressed. Conclusions Peripheral isolated lymph nodes, including right supraclavicular lymph node, can recur without a macroscopic abdominal lesion. Clinicians should carefully examine peripheral lymph nodes for recurrence.</p

The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair.

The activating transcription factor 2 (ATF2) is a member of the ATF/cAMP-response element-binding protein family of basic-leucine zipper proteins involved in cellular stress response. The transcription potential of ATF2 is enhanced markedly by NH2-terminal phosphorylation by c-Jun NH2-terminal kinase (JNK) and mediates stress responses including DNA-damaging events. We have observed that four DNA-damaging agents (cisplatin, actinomycin D, MMS, and etoposide), but not the cisplatin isomer, transplatin, which does not readily damage DNA, strongly activate JNK, p38, and extracellular signal-regulated kinase (ERK), and strongly increase phosphorylation and ATF2-dependent transcriptional activity. Selective inhibition studies with PD98059, SB202190, SP600125, and the dominant negative JNK indicate that activation of JNK but not p38 kinase or ERK kinase is required for the phosphorylation and transcriptional activation of ATF2. Stable expression of ATF2 in human breast carcinoma BT474 cells increases transcriptional activity and confers resistance to the four DNA-damaging agents, but not to transplatin. Conversely, stable expression of a dominant negative ATF2 (dnATF2) quantitatively blocks phosphorylation of endogenous ATF2 leading to a marked decrease in transcriptional activity by endogenous ATF2 and a markedly increased sensitivity to the four agents as judged by decreased cell viability. Similarly, application of SB202190 at 50 micro m or SP600125 inhibited JNK activity, blocked transactivation, and sensitized parental cells to the four DNA-damaging drugs. Moreover, the wild type ATF2-expressing clones exhibited rapid DNA repair after treatment with the four DNA-damaging agents but not transplatin. Conversely, expression of dnATF2 quantitatively blocks DNA repair. These results indicate that JNK-dependent phosphorylation of ATF2 plays an important role in the drug resistance phenotype likely by mediating enhanced DNA repair by a p53-independent mechanism. JNK may be a rational target for sensitizing tumor cells to DNA-damaging chemotherapy agents

A rare case of ovarian carcinosarcoma with squamous cell carcinoma

Abstract Background Ovarian carcinosarcoma, which contains sarcomatous and carcinomatous components, is a very rare tumor. The carcinomatous component is often adenocarcinoma, and squamous cell carcinoma is extremely rare. We herein report a case of ovarian carcinosarcoma in which the carcinomatous component was squamous cell carcinoma. Case presentation A 68-year-old woman presented with a huge ovarian tumor with a clinical diagnosis of malignant tumor of the ovary. She underwent hysterectomy, bilateral adnexectomy, omentectomy and lymphadenectomy. Histologically, the tumor cells showed undifferentiated pleomorphic sarcoma as the sarcomatous component and squamous cell carcinoma as the carcinomatous component. The final diagnosis was ovarian carcinosarcoma with squamous cell carcinoma in the carcinomatous component, stage IIIA1. Postoperatively, the patient was treated with six cycles of combination chemotherapy with paclitaxel and carboplatin as adjuvant therapy. The patient was free of disease at 45 months’ follow-up consultation. Conclusion This is a rare report of ovarian carcinosarcoma with an epithelial component composed of squamous cell carcinoma. Combination chemotherapy with paclitaxel and carboplatin may be an effective choice as adjuvant chemotherapy in cases of ovarian carcinosarcoma including squamous cell carcinoma

MRI appearance of ovarian serous borderline tumors of the micropapillary type compared to that of typical ovarian serous borderline tumors: radiologic-pathologic correlation

Abstract Background Serous borderline tumor (SBT) of the micropapillary type (SBT-MP) became one of the major pathological SBT diagnoses in addition to typical SBT, and was also defined as “non-invasive” low-gradeserous carcinoma according to the World Health Organization (WHO) classification in 2014. In this study, we investigated the MRI appearance of SBT-MP compared to that of typical SBT in order to identify specific imaging features of SBT-MP that correspond to pathological findings. Methods MR images of 6 histologically proven ovarian SBT-MP in four patients and 14 typical SBT in ten patients were reviewed retrospectively. Images were evaluated for laterality, size and morphology of the lesion and the solid component (SC) and signal intensity (SI) of the SC. MRI findings were correlated with pathological findings. Results The patients with SBT-MP (mean 26.3 years) were younger than those with typical SBT (mean 44.5 years). Postoperative staging in patients with SBT-MP was II in two and III in two cases, while staging for typical SBT was I in seven, II in one and III in two cases. The morphologic patterns of SBT-MP were a unilateral cystic mass with intracystic mural nodules (CwMN) (n = 2), bilateral solid papillary masses (SM), and bilateral SM with CwMN. The pattern of typical SBT was CwMN (n = 13) in all but one lesion (SM with CwMN). All SCs showed inhomogeneous slight hyperintensity on T2 weighted images (WI) and high SI on diffusion-WI (DWI) except for in one typical SBT. Although diffuse proliferation of the tumor cells in micropapillary projections with little stroma seemed to correspond to inhomogeneous slightly hyperintense foci in SC on T2WI and high SI on DWI, similar MR findings were observed in typical SBT in all lesions on T2WI and 11 of 12 lesions on DWI. In typical SBT, inhomogeneous slightly hyperintense foci in SC on T2WI and high SI on DWI corresponded to highly cellular foci with densely branched papillae. Conclusion Pathological findings and clinical behavior of SBT-MP differed from those of typical SBT, but morphology and SI of SC on MRI were similar, with papillary projections demonstrating inhomogeneous slight hyperintensity on T2WI and high SI on DWI

Diversity of imaging features of ovarian sclerosing stromal tumors on MRI and PET-CT: a case report and literature review

Abstract Background Sclerosing stromal tumors (SST) are rare, benign tumors classified as sex cord stromal tumors. To our knowledge, positron emission tomography with computed tomography (PET-CT) findings of SST have only been described in one report and imaging findings on diffusion-weighted imaging (DWI) have only been described in three reports. Characteristic imaging features of SST on PET-CT and DWI have not yet been identified. Here we report a case of multilocular SST with solid components showing mild FDG uptake and slight hyperintensity on DWI, and reviewed the literature. Case presentation Seventeen-year-old woman presented with a complaint of abdominal pain and was admitted due to infectious colitis. Ultrasonography incidentally revealed a multiseptated cystic mass in the pelvis. Magnetic resonance imaging (MRI) showed a large multilobulated cystic mass with irregularly thickened septa and solid components originating in the left adnexa. On T2WI, the cystic components had the same signal intensity (SI) as water, and the irregularly thickened septa and solid components showed intermediate SI higher than the SI of the uterine myometrium. The septa and solid components also showed early strong enhancement on contrast-enhanced T1WI and slight hyperintensity on DWI. The PET-CT showed mild FDG uptake in the solid components of the tumor (SUV: 2.11). According to previous articles, the morphology of SSTs are various; solid mass, well-circumscribed multilobular mass, well-demarcated mass, and multilocular cysticmass. According to the reports describing DWI findings of SST, the SI varies from significant hyperintensity to slightly hyperintensity like in this case. Only one report describing PET-CT findings of SST showed intense FDG uptake (SUV max: 7.0). Conclusion The findings on DWI and PET-CT of our case and the past reports describing PET and DWI findings of SSTs are not consistent. The wide variety of the signal intensity on MRI and FDG uptake on PET could be due to the pathological diversity caused by the cellular areas undergoing collagenous sclerosis, which transforms the tumor into admixture of the collagen and the densely fibrous components with edema