Tumor cell plasticity in endometrioid carcinoma is regulated by neuronal membrane glycoprotein M6-b.

Tumor cell plasticity and tumor heterogeneity are involved in therapy resistance. Cancer stem cells (CSCs) refer to tumor cells that have the ability to self-renew, and generate the diverse cells that comprise the tumor and complicate tumor heterogeneity. In recent years, CSCs have been reported to emerge from non-CSCs, which is known as tumor cell plasticity; however, the mechanism has not been fully elucidated. The present study investigated tumor cell plasticity from the viewpoint of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) activity, which is one of the markers of CSCs. In the endometrioid carcinoma cell line HEC-1B, the ALDH1A1-low population spontaneously yielded an ALDH1A1-high population, mimicking tumor cell plasticity, and it was revealed that the mixture of the ALDH1A1-high population with the ALDH1A1-low population sometimes accelerated the transition from an ALDH1A1-low to ALDH1A1-high population. Two distinct HEC-1B sublines were established. One of the two sublines accelerated such a transition and the other did not show such acceleration. In the former subline, the effect of the ALDH1A1-high population was abolished when the direct cell-cell contact between ALDH1A1-high and ALDH1A1-low populations was inhibited. By comparing the two sublines, the neuronal membrane glycoprotein M6-b (GPM6B) was identified as the candidate mediating tumor cell plasticity. GPM6B was expressed in the border of ALDH1A1-expressing tumor cells and non-expressing tumor cells in clinical samples of EC. Notably, knockout of GPM6B decreased ALDH1A1 expression, whereas its overexpression increased the expression of ALDH1A1, suggesting that GPM6B mediated the induction of ALDH1A1 and the plasticity of CSCs.

An immature inhibin-α-expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis.

Inhibin-α, a member of transforming growth factor-ß, is elevated in multiple tumors, but its specific roles are poorly understood. Here, we examined the feature of inhibin-α-expressing cells in ovarian tumors. Immunohistochemically, inhibin-α-expressing tumor cells were detected only in ovarian clear cell carcinoma (OCCC) among various types of ovarian tumors. By comparing the expression of inhibin-α and Ki-67, inhibin-α-expressing tumor cells were revealed to be less proliferative. When spheroids and chemoresistant cells were derived from OCCC cell lines, the expression level of inhibin-α was elevated, and that of an immature marker, aldehyde dehydrogenase, was also elevated. In consistent with this, inhibin-α expression was correlated with other immature markers, such as OCT3/4 and SOX2, and inversely correlated with proliferative marker MKI67 in public database on OCCC. Knockdown of inhibin-α in OCCC cell decreased chemoresistance. Moreover, prognostic analysis with 69 surgically resected OCCC cases revealed that the increased inhibin-α expression was an independent unfavorable prognostic factor. These findings suggested that inhibin-α-expressing subpopulation of OCCC tumor cells appeared to be less proliferative, immature, and angiogenic and to be related to acceleration of malignant progression.

Effect of glutamine on lymphoplasmacytic lymphoma, especially on the viewpoint of the differentiation into vulnerable subpopulation.

Glutamine (Gln) is important not only for cell proliferation but also for differentiation. Although Gln is essential for plasmacytic differentiation of lymphocytes, no study has been done on the effect of Gln on differentiation of tumor cells, such as lymphoma. Here we examined the effect of Gln on plasmacytic differentiation of lymphoplasmacytic lymphoma (LPL) with its cell lines, MWCL-1 and RPCI-WM1. Gln promoted plasmacytic differentiation of LPL, and p38 MAPK signaling pathway mediated such differentiation. We previously reported that the subpopulation with plasmacytic differentiation was vulnerable to apoptosis in LPL. Although it is difficult to lead these findings to the radical therapy, they might help the treatment of LPL, in which stimulation of p38 MAPK by Gln induced differentiation of LPL into vulnerable subpopulation.

Successful radiotherapy for endometrial serous carcinoma with local repeated recurrence.

The incidence of endometrial serous carcinoma (ESC) has been increasing, and ESC is resistant to treatment. We report a patient with ESC who responded to radiotherapy for multiple recurrences. The first recurrence was detected in the vaginal wall and left internal iliac lymph node 5 months after the initial treatment. Concurrent chemoradiotherapy (CCRT) was administered. Radiation was delivered using the intensity modulated radiation therapy technique. The second recurrent tumor was detected in the right internal iliac lymph node after 4 months, and CCRT was conducted. After 4 months, the third recurrence was detected in the right common iliac node, and CCRT was performed. After 8 months, the fourth recurrence was detected in the horizontal portion of the duodenum, and radiotherapy was administered. After 9 months, the fifth recurrence was detected in the vaginal wall. Interstitial brachytherapy was conducted. Grade 2 gastrointestinal injury, nausea and radiodermatitis were observed. During the subsequent 13-month follow-up, there has been no recurrence. Although ESC is resistant to treatment, radiotherapy could be effective in some cases. Even when multiple recurrences occur, radiotherapy may be considered a treatment option if the irradiation level is permissible.

[Clinical Study to Determine the Dose Intensity of BEP Chemotherapy for Ovarian Malignant Germ Cell Tumors].

A standard regimen for ovarian malignant germ cell tumors is bleomycin, etoposide, cisplatin(BEP)chemotherapy. Adherence to a treatment schedule of every 21 days has been reported to be important. However, the incidence of febrile neutropenia( FN)and the optimaluse of granulocyte-colony stimulating factor(G-CSF)are unclear because of the low incidence of ovarian malignant germ cell tumors. We experienced 2 cases of ovarian malignant germ cell tumors that received BEP therapy after fertility-conserving surgery. In 1 case, we delayed drug administration in the first cycle because of FN. However, in order to maintain dose intensity(DI), we performed chemotherapy every 21 days by shortening the rest period. Myelosuppression may be severe in the first cycle of BEP therapy; however, it may be possible to adhere to the treatment schedule by using primary prophylactic administration of G-CSF.

[Outcomes of Tertiary Debulking Surgery(TDS)for Re-Recurrent Ovarian Cancer].

The survival of patients with recurrent ovarian cancer who have completed secondary debulking surgery (SDS) has been shown to increase. However, whether tertiary debulking surgery (TDS) aimed at complete surgery is useful in patients with a second recurrence is unclear. Eight patients who had undergone SDS were treated after a second recurrence in our hospital. Their medical records were retrospectively reviewed. Consequently, TDS was performed in 4 of the patients (TDSgr). All 4 patients underwent complete debulking surgery, 2 patients received blood transfusions, and none had serious postoperative complications. The median treatment free interval (TFI) from recurrence surgery to the second recurrence was 16 months (range, 9-23 months), and the median TFI after the second recurrence was 30.5 months (range, 15-69 months). Meanwhile, the median TFI after the second recurrence was 7.5 months (range, 1-31 months) in the 4 patients who did not undergo TDS (non-TDSgr). The median survival times after the second recurrence in TDSgr and non-TDSgr were 53 months (range, 41-69 months) and 12 months (range, 2-30 months), respectively. When complete surgery is indicated in patients with a second recurrent ovarian cancer after SDS, in case of good physical condition with single or multiple recurrent lesions, TDS may increase survival and TFI.