Hironori Kunisue

Expression of vascular endothelial growth factor (VEGF) family members in breast cancer

Vascular endothelial growth factor (VEGF)‐A is known to play an important role in tumor angiogenesis. Three additional members of the VEGF family, VEGF‐B, ‐C and ‐D, have recently been discovered. VEGF‐C and VEGF‐D are ligands for VEGF receptor‐3, which is expressed in the endothelium of lymphatic vessels. The expression of VEGF‐C is known to be associated with the development of lymphatic vessels. Therefore, it is conceivable that VEGF‐C and VEGF‐D might play a role in the development of lymphatic vessels in solid tumors. To obtain some clue as to this role, we developed a semi‐quantitative reverse transcription‐polymerase chain reaction method to investigate the mRNA expression levels of each VEGF family member in breast cancer. All the VEGF family members were expressed at different levels in seven human breast cancer cell lines explored. Although VEGF‐A and VEGF‐B expressions were detected in both node‐positive and node‐negative breast tumors, VEGF‐C expression was detected only in node‐positive tumors. VEGF‐D expression was detected only in an inflammatory breast cancer and a tumor which developed an inflammatory skin metastasis. These findings suggest a possible relationship between the expression level of VEGF‐C and/or VEGF‐D and the development of lymphatic tumor spread.

Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2

Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive breast carcinomas, butmost of these tumours become resistant to anti-oestrogen. It has been suggested that anti-oestrogen therapy may induce a HER2signalling pathway in breast cancer cells and this may cause resistance to anti-oestrogen. Thus, it is conceivable that combinedtherapy with anti-oestrogen and anti-HER2 antibody might be more effective. In the present study, we investigated the effect ofcombined treatment with a humanized anti-HER2 monoclonal antibody, rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, onthe cell growth of three human breast cancer cell lines which respectively express different levels of ER and HER2. The combinedtreatment enhanced the growth inhibitory effect on ML-20 cells, which express a high level of ER and a moderate level of HER2, butshowed no additive effect on either KPL-4 cells, which express no ER and a moderate level of HER2, or MDA-MB-231 cells, which express no ER and a low level of HER2. It is also suggested that both the antibody and anti-oestrogen induce a G1–S blockade and apoptosis. These findings indicate that combined treatment with anti-HER2 antibody and anti-oestrogen may be useful for thetreatment of patients with breast cancer expressing both ER and HER2.

Paradoxical Hormone Responses of KPL-1 Breast Cancer Cells in vivo: A Significant Role of Angiogenesis in Tumor Growth

In our previous study, the growth of KPL-1 human breast cancer cells was found to be stimulated by an antiestrogen, ICI 182, 780, and inhibited by 17 β-estradiol (E2) in vivo but not in vitro. To investigate the action mechanisms of these paradoxical responses, the effects of E2, ovariectomy (Ovex) and medroxyprogesterone acetate (MPA) on the growth, angiogenesis, apoptosis and expression of vascular endothelial growth factor (VEGF) were investigated. E2 stimulated the growth of KPL-1 cells but MPA inhibited it in vitro. In contrast, E2 propionate inhibited the growth of KPL-1 cells in female nude mice but Ovex and MPA stimulated it. E2 propionate suppressed angiogenesis and increased apoptosis in KPL-1 tumors, but Ovex and MPA promoted angiogenesis and decreased apoptosis. Both mRNA expression and secretion of VEGF were stimulated by MPA in KPL-1 cells, but in E2-dependent ML-20 cells they were both inhibited by MPA. E2 did not significantly influence VEGF expression in either cell line. These findings suggest that the abnormal modulation of VEGF expression by MPA and of the other angiogenic factor by E2 are responsible for the paradoxical growth responses of KPL-1 cells in vivo. To support this hypothesis, an antiangiogenic agent, TNP-470, was administered to mice bearing KPL-1 tumors. TNP-470 significantly inhibited the growth of KPL-1 tumors stimulated by MPA. Antiangiogenic agents may be effective for the treatment of hormone-refractory breast cancer.

Changes of expression level of the differentiation markers in papillary thyroid carcinoma under thyrotropin suppression therapy in vivo immunohistochemical detection of thyroglobulin, thyroid peroxidase, and thyrotropin receptor

Differences in the expression levels of Thyroglobulin (Tg), Thyroid peroxidase (TPO) and thyrotropin receptor (TSH‐R) in primary and recurrent specimens under a suppressive serum TSH condition were elucidated in 26 papillary carcinoma patients.

Metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia: report of a case.

We report a unique case of metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia. A 48-year-old man was referred to our hospital for treatment of a thyroid tumor and right submandibular masses. A tumor, 2 cm in its largest dimension, was palpated in the right lobe of the thyroid gland. The masses in the submandibular region measured up to 3 cm in diameter. Each submandibular tumor had a cystic cavity containing slightly opaque fluid. Aspiration cytology of the thyroid established a diagnosis of papillary carcinoma. Aspirated material from the cystic cavity of one of the submandibular masses contained only keratinized material with a thyroglobulin level of 175 ng/ml. The patient underwent a total thyroidectomy with modified radical neck dissection. Microscopic examination of the resected specimen confirmed a diagnosis of papillary carcinoma of the thyroid, as well as well-differentiated squamous cell carcinoma with cystic changes in the submandibular lymph nodes. Focal immunoreactivity for thyroglobulin, combined with the absence of any other possible primary lesions in the head and neck region, suggested metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia.