Mecker Moller

Comparative analysis of volatile metabolomics signals from melanoma and benign skin: a pilot study.

The analysis of volatile organic compounds (VOC) as biomarkers of cancer is both promising and challenging. In this pilot study, we used an untargeted approach to compare volatile metabolomic signatures of melanoma and matched control non-neoplastic skin from the same patient. VOC from fresh (non-fixed) biopsied tissue were collected using the headspace solid phase micro extraction method (HS SPME) and analyzed by gas chromatography and mass spectrometry (GCMS). We applied the XCMS analysis platform and MetaboAnalyst software to reveal many differentially expressed metabolic features. Our analysis revealed increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma. The identity of these compounds was confirmed by comparison with chemical standards. Increased levels of these fatty acids are likely to be a consequence of up-regulated de novo lipid synthesis, a known characteristic of cancer. Increased oxidative stress is likely to cause an additional increase in lauric acid. Implementation of this study design on larger number of cases will be necessary for the future metabolomics biomarker discovery applications.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery.

Predictors of locoregional outcome in patients receiving neoadjuvant therapy and postmastectomy radiation

The objective of this study was to identify predictors of locoregional recurrence (LRR) after neoadjuvant therapy (NAT) and postmastectomy radiation (PMRT) in a cohort of patients with stage II through III breast cancer and to determine whether omission of the supraclavicular field had an impact on the risk of LRR.

A case report - Volatile metabolomic signature of malignant melanoma using matching skin as a control

Melanoma is the most serious form of skin cancer. The quest for melanoma diagnostic biomarkers is paramount since early detection of melanoma and surgical excision represent the only effective treatment of this capricious disease. Our recent study tested the hypothesis that melanoma forms a unique volatile signature that is different than control, healthy tissue. Here, we are reporting a case study, the analysis of the volatile metabolic signature of a malignant melanoma using matched, non-neoplastic skin tissue from the same patient as a control. This is a significant improvement in the methodology, since it is well known that diet, skin type, genetic background, age, sex and environment all contribute to individual variation in the skin volatile signature. In the present study, we have identified 32 volatile compounds; 9 volatile compounds were increased in melanoma when compared to normal skin and 23 volatile compounds were detected only in melanoma and not in normal skin. Out of these 32 compounds, 10 have been reported previously by our group, thus confirming our results and adding additional confidence in our untargeted metabolomics approach for detection of melanoma biomarkers.

Malignant granular cell tumor of the back: A case report and review of the literature

Malignant granular cell tumors are rare, intensely aggressive entities. This paper presents a case of a large rapidly recurrent malignant granular cell tumor with regional and distal metastases on the back of a 54-year-old Cuban man. The primary tumor recurred within six months of the original wide local excision and with satellite lesions apparent at twelve months, and the mass was diagnosed using the histological criteria established by Fanburg-Smith et al. for malignant granular cell tumors. By fifteen months, right axillary lymphadenopathy, multiple satellite lesions, pulmonary nodules, and distant metastasis in the right thigh were present. At sixteen months, wide local excision of recurrent mass and local satellite masses along with right axillary dissection and placement of Integra with subsequent split-thickness skin graft were performed by surgical oncology and plastic surgery teams. The surgical specimen measured 32.0 × 13.5 × 5.5 cm, containing multiple homogeneous masses with the largest mass 22.0 × 9.0 × 4.6 cm. Following surgery, patient was started on Pazopanib 800 mg/day based on phase III randomized trial data in the treatment of soft tissue sarcomas showing this as a potential novel therapy for malignant granular cell tumors.

Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis

Mesenchymal stem cells-derived fibroblasts (MSC-DF) constitute a significant portion of stromal fibroblasts in the tumor microenvironment (TME) and are key modulators of tumor progression. However, the molecular mechanisms that determine their tumor-regulatory function are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that selectively controls the regulatory role of MSC-DF in melanoma metastasis. We demonstrate that the Notch1 pathways activity is inversely correlated with the metastasis-regulating function of fibroblasts and can determine the metastasis-promoting or -suppressing phenotype of MSC-DF. When co-grafted with melanoma cells, MSC-DFNotch1−/− selectively promote, while MSC-DFN1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DFNotch1−/− and MSC-DFN1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro. Additionally, when co-cultured with metastatic melanoma cells in vitro, MSC-DFNotch1−/− support, while MSC-DFN1IC+/+ inhibit melanoma cells in the formation of spheroids. These findings expand the repertoire of Notch1 signaling as a molecular switch in determining the tumor metastasis-regulating function of MSC-DF. We also identified Wnt-induced secreted protein-1 (WISP-1) as a key downstream secretory mediator of Notch1 signaling to execute the influential role of MSC-DF on melanoma metastasis. These findings reveal the Notch1—WISP-1 axis as a crucial molecular determinant in governing stromal regulation of melanoma metastasis; thus, establishing this axis as a potential therapeutic target for melanoma metastasis.

Bilateral pseudoangiomatous stromal hyperplasia tumors in axillary male gynecomastia: report of a case.

Pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferation of breast stromal cells with a complex pattern of interanastomosing spaces lined by myofibroblasts. The exact etiology is still unknown, but a proliferative response of myofibroblasts to hormonal stimuli has been postulated. PASH is a relatively common incidental finding in breast tissue removed for other reasons and rarely manifests as a localized mass. Fewer than 150 cases of tumoral PASH have been reported since it was first described in 1986. Although PASH tends to grow over time, most lesions are cured by surgical excision and the prognosis is excellent. We report an unusual case of bilateral axillary tumoral PASH in a 44-year-old man. Awareness of this disease is important when considering the differential diagnosis of axillary masses. To our knowledge, only one other case of unilateral axillary tumoral PASH in a male patient has been described in English and this is the first case of PASH occurring in male bilateral axillary gynecomastia.

International Society for Cell and Gene Therapy of Cancer 2009 Annual Meeting Held in Cork, Ireland

The International Society for Cell and Gene Therapy (ISCGT) of Cancer annual meeting was held from September 2 through September 4, 2009, in Cork, Ireland ( www.iscgt2009.com ). The conference was held in conjunction with the Irish Society for Gene and Cell Therapy third annual meeting, and brought together scientists and clinicians from around the world in a country developing its knowledge economy. Next years ISCGT meeting will be held in Doha, the capital of Qatar ( www.iscgt.net ), from September 27 through September 29, 2010.

Abstract 5010: Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts

Objectives. The tumor microenvironment (TME) is an emerging therapeutic target for cancer treatment. Cancer-associated fibroblasts (CAF) play a crucial role in cancer progression. We aim to target TME by altering intracellular signaling which determines the biological function of CAF. We have recently showed that the Notch signaling pathway likely functions as a molecular switch in controlling the tumor regulatory role of CAF in animal models and experimentally created “CAF”. Here, we investigated the status of Notch signaling in human melanoma-associated fibroblasts (MAF) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAF alter their tumor-regulating function. Methods. We examined levels of Hes1, a canonical Notch target, in MAF of human malignant melanoma at different stages (I-IV) and fibroblasts in either adjacent or non-adjacent normal skin tissues using tissue microarray. MAF were isolated from human metastatic melanoma tissues. Notch pathway RT2-PCRArray and immunoblot were used to assess Notch pathway activity in MAF versus normal human dermal fibroblasts. Activation of Notch signaling pathway in MAF was achieved by lentiviral vector encoding active form of Notch1 (NIC). The effect of Notch1-engineered MAF on melanoma growth was tested by in vitro co-cultures and in a mouse co-xenograft model (n=6/group). Tumor angiogenesis was analyzed by immunochemistry. Results. MAF expressed decreased levels of Hes1 compared with adjacent skin fibroblasts. Isolated MAF also exhibited lower Notch activity than normal human dermal fibroblasts. Notch1-engineered MAF significantly inhibited melanoma cell growth in vitro (p Conclusions. Notch pathway activity is down-regulated in MAF. Increase of Notch pathway activity confers MAF with inhibition to melanoma growth and tumor angiogenesis. Our study demonstrates that Notch signaling is a critical molecular switch in determining the tumor regulatory role of MAF and provides potential targets for cancer therapeutic interventions on the TME. Citation Format: Hongwei Shao, Mecker G. Moller, Long Cai, Leiming Zhang, Zhao-Jun Liu. Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5010. doi:10.1158/1538-7445.AM2017-5010

Abstract 4085: Notch1 signaling determines melanoma-regulating role of tumor stromal fibroblasts

Objectives. Tumor stromal fibroblasts are crucial in regulating tumor growth, invasion and metastasis, yet the molecular mechanisms that determine the tumor regulatory role of stromal fibroblasts remains unknown. Here, we uncover the Notch1 signaling pathway as a molecular determinant that controls the tumor regulatory role of tumor stromal fibroblasts in melanoma growth and invasion. Methods. Murine melanoma cells B16-F10, stably transduced with Luciferase 2 (Luc2)/lentivirus, were xenografted on the skin of two new mouse lines: the Gain-Of-Function of Notch1 (GOFNotch1: Fsp1.Cre+/-;ROSALSL-N1IC+/+) and Loss-Of-Function of Notch1 (LOFNotch1: Fsp1.Cre+/-;Notch1LoxP/LoxP+/+), respectively. GOFctrl (FSP1.Cre-/-;ROSALSL-N1IC+/+) and LOFctrl (FSP1.Cre-/-; Notch1LoxP/LoxP+/+) mice were used as control. Tumor growth was measured based on tumor weight and melanoma local invasion were examined by HE 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4085.