Yuko Yoshio

Endocrine Disrupter Bisphenol A Increases In Situ Estrogen Production in the Mouse Urogenital Sinus

The balance between androgens and estrogens is very important in the development of the prostate, and even small changes in estrogen levels, including those of estrogen-mimicking chemicals, can lead to serious changes. Bisphenol A (BPA), an endocrine-disrupting chemical, is a well-known, ubiquitous, estrogenic chemical. To investigate the effects of fetal exposure to low-dose BPA on the development of the prostate, we examined alterations of the in situ sex steroid hormonal environment in the mouse urogenital sinus (UGS). In the BPA-treated UGS, estradiol (E2) levels and CYP19A1 (cytochrome P450 aromatase) activity were significantly increased compared with those of the untreated and diethylstilbestrol (DES)-treated UGS. The mRNAs of steroidogenic enzymes, Cyp19a1 and Cyp11a1, and the sex-determining gene, Nr5a1, were up-regulated specifically in the BPA-treated group. The up-regulation of mRNAs was observed in the mesenchymal component of the UGS as well as in the cerebellum, heart, kidney, and ovary but not in the testis. The number of aromatase-expressing mesenchymal cells in the BPA-treated UGS was approximately twice that in the untreated and DES-treated UGS. The up-regulation of Esrrg mRNA was observed in organs for which mRNAs of steroidogenic enzymes were also up-regulated. We demonstrate here that fetal exposure to low-dose BPA has the unique action of increasing in situ E2 levels and CYP19A1 (aromatase) activity in the mouse UGS. Our data suggest that BPA might interact with in situ steroidogenesis by altering tissue components, such as the accumulation of aromatase-expressing mesenchymal cells, in particular organs.

Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo

Activation of tumor-stromal interactions is considered to play a critical role in the promotion of tumorigenesis. To discover new therapeutic targets for hormone-refractory prostate tumor growth under androgen ablation therapy, androgen-sensitive LNCaP cells and the derived sublines, E9 (androgen-low-sensitive), and AIDL (androgen-insensitive), were recombined with androgen-dependent embryonic rat urogenital sinus mesenchyme (UGM). Tumors of E9 + UGM and AIDL + UGM were approximately three times as large as those of LNCaP + UGM. Tumors grown in castrated hosts exhibited reduced growth as compared with those in intact hosts. However, in castrated hosts, E9 + UGM and AIDL + UGM tumors were still approximately twice as large as those of LNCaP + UGM. Cell proliferation in tumors of E9 + UGM and AIDL + UGM grown in castrated host, was significantly higher than that in tumors of LNCaP + UGM. In vitro, expression of fibroblast growth factor (FGF)-2 and IGF-I, but not FGF-7 mRNA, was significantly reduced in UGM under androgen starvation. In cell culture, E9 cells were responsive to FGF-2 and FGF-7 stimulation, while AIDL responded to FGF-7 and IGF-1. Expression of FGFR1 and FGFR2 was considerably higher in E9 than those in LNCaP, similarly expression of FGFR2 and IGF-IR were elevated in AIDL. These data suggest that activation of prostate cancer cell growth through growth factor receptor expression may result in the activity of otherwise androgen-independent stromal growth factor signals such as FGF-7 under conditions of androgen ablation.

Effect of transforming growth factor α overexpression on urogenital organ development in mouse.

Transforming growth factor-α (TGFα) promotes cell proliferation by binding to the epidermal growth factor receptor (EGFR). TGFα and EGFR overexpression have been reported in various human cancers. However, whether TGFα induces cancer by itself is unknown in urogenital organs. To investigate whether TGFα overexpression induces carcinogenesis in urogenital organs, we analyzed the phenotypes of urogenital organs in male TGFα transgenic (TG) mice of the CD1 strain. Urogenital organs including the kidney, bladder, prostate, seminal vesicles, testes, and epididymis were isolated from 4- to 48-week-old TGFα TG and wild-type (WT) CD1 mice. Prostates were separated into anterior prostate (AP), dorsolateral prostate (DLP), and ventral prostate (VP). Neither tumor formation nor epithelial hyperplasia was observed in the TGFα TG mouse urogenital organs that we have investigated. Histopathologically, in prostate, we found an increased number of p63-positive basal epithelial cells in the TGFα TG mice AP and DLP. There was no morphological change in the stromal component, such as hypercellular stroma or fibrosis. However, bladder weight was greater in TGFα TG mice than that in WT mice, and distended bladders were observed macroscopically in 19 of 20 TGFα TG mice over 20 weeks of age. Ki67 labeling index was increased significantly in the TGFα TG mouse urethral epithelium, whereas neither epithelial hyperplasia nor hypertrophy was observed. In conclusion, our results suggest that TGFα overexpression in mouse urogenital organs alone may not be responsible for tumor formation and epithelial hyperplasia, but is involved in bladder outlet obstruction.

Renal angiomyolipoma with para-aortic lymph node involvement: Letter to the Editor

To the Editor: Renal angiomyolipomas (AMLs) are uncommon benign tumors comprising varying proportions of blood vessels, smooth muscle, and adipose tissue, and some renal AMLs are complicated by tuberous sclerosis complex (TSC). This tumor was previously regarded as a hamartoma, but it is now classified into a family of neoplasms with perivascular epithelioid-cell differentiation (PEComas) according to the World Health Organization (WHO) classification. In most cases, renal AMLs show only one lesion and can be diagnosed preoperatively on ultrasonography or computed tomography (CT). However, renal AMLs occasionally accompany metasynchronous lymph node involvement, and this condition could mimic a metastasizing malignant tumor. Herein, we report a case of a renal AML with para-aortic lymph node involvement and discuss the possible underlying pathogenesis. A 62-year-old woman visited her family physician because a palpable swelling was discovered in her left flank during a check-up. Abdominal CT revealed a tumor in the left kidney, and the patient was admitted to our hospital for further examination. On admission, the mass was in the upper left abdomen, and its maximum diameter was 15 cm. She had no family history of TSC, and laboratory findings were normal. Plain abdominal CT showed a tumor in the left kidneys lower pole; the kidney measured 14 12 9 cm, with a preserved shape. Abdominal contrast-enhanced CT showed early-phase hyperdensity (Fig. 1a) and delayedphase hypodensity. Enlarged lymph nodes were observed in the para-aortic area (Fig. 1a) and left renal hilum. Abdominal magnetic resonance imaging (MRI) revealed multiple spotty, high-intensity areas in the tumor on T1weighted (Fig. S1a) and T2-weighted images (Fig. S1b). There were no abnormalities on plain abdominal CT, abdominal contrast-enhanced CT, or abdominal MRI on the opposite side of the left kidney. Angiographic imaging showed angioneogenesis and aneurysm formation in the tumor (Fig. S2). Thus, a renal cell carcinoma (RCC) was suspected. Total resection of the left kidney with dissection of the para-aortic lymph nodes was performed 1 day after transarterial embolization (TAE). The patients postoperative course was uneventful. No recurrence or metachronous growth has been observed for 10 years postoperatively, even though the patient did not receive adjuvant chemotherapy. Macroscopically, the tumor was in the left kidneys lower pole, and it was 17 10.5 10 cm in size (Fig. 1b). The specimens cut surface was tan-white and revealed multiple nodes showing aneurysms. Hemorrhagic foci and partially necrotic areas were also observed on the cut surface, possibly due to the TAE. Eleven lymph nodes were dissected, and their cut surfaces were also tan-white. The lymph nodes ranged in size from 1 cm to 3.8 cm. Histologically, the tumor was demarcated from the normal renal parenchyma. It comprised three elements: numerous blood vessels (Fig. S3) and streams of smooth muscle components embedded within adipose tissue (Fig. 1c). No atypia or mitotic figures were observed in any cellular components. Lymph nodes from the para-aortic area contained similar components (Fig. 1d, Fig. S4a–c). Immunohistochemical studies confirmed that the blood vessel components were positive for CD34 (Fig. S5a), the smooth muscle components were positive for aSMA (Fig. S5b), and the adipose tissues were positive for S-100 protein (Fig. S5c). The tumor cells were also positive for HMB45 (Fig. S5d), and they were negative for cytokeratin AE1/AE3, epithelial membrane antigen (EMA), and leukocyte common antigen (LCA). Therefore, we diagnosed the tumor as an AML with para-aortic lymph node involvement. In our case, the AML in the para-aortic lymph nodes cooccurred with a tumor in the left kidney. The patient has shown no recurrence or metachronous growth for 10 years after surgery, even though she did not receive adjuvant chemotherapy. This benign behavior and the benign histological appearance of the tumor suggest that the lymph node involvement in our case represented a multicentric origin of the AML rather than tumor metastasis. Busch et al. reported two cases of AMLs with lymph node involvement; their patients did not have evidence of TSC. The benign appearance of the renal and lymph node AML cells made them believe that the tumors had arisen from a multicentric origin. Bloom et al. reported three cases of TSC-complicated renal AMLs with lymph node involvement. All three patients showed a long-term postoperative course without tumor recurrence. The authors noted that the TSC complications strengthened the theory for multicentricity. 2 Manabe et al. described the case of a patient with a renal AML with lymph node involvement. The patient showed no signs of tumor recurrence during a 3-year postoperative follow-up period. Based on the benign postoperative course, they concluded that the lymph node lesion probably represented a multicentric occurrence or choristomatous growth of AML.