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S | Carcinogenesis & Cancer Genetics 074 Bullous leukemia cutis in a patient with T-cell prolymphocytic leukemia Q Jiang, S Siu, S Onder Alpdogan, A Gochoco, J Gong, J Lee and J Sahu 1 Dermatology, Thomas Jefferson University, Philadelphia, PA, 2 Pathology, Thomas Jefferson University, Philadelphia, PA and 3 Medical Oncology, Thomas Jefferson University, Philadelphia, PA T-cell prolymphocytic leukemia (T-PLL) is a rare neoplasm of mature T lymphocytes. Cutaneous involvement, e.g., leukemia cutis (LC), is a characteristic symptom of T-PLL and appears in up to one-third of cases. LC may follow, precede or occur concomitantly with the diagnosis of systemic leukemia, however, vesiculo-bullous LCs are rare. So far, few were reported in chronic lymphocytic leukemia, but none in T-PLL. T-PLL is a relatively unknown disease in the field of dermatology, and moreover, variable leukemic cutaneous manifestations, especially the non-specific lesions of bullous LC, make it clinically difficult to distinguish from other non-specific lesions. We report here a case of leukaemia cutis with vesiculo-bullous lesions in a patient who was recently diagnosed with T-PLL and has been on chemotherapy. A skin biopsy specimen showed dense infiltration of small lymphocytes in the dermis, and subsequent immunogenotyping confirmed the presence of leukemia cells in the same patterns of previous biopsies of the lymph node. To our knowledge, this is the first report of vesiculo-bullous LC in a patient with T-PLL. LC is an indicator of poor prognosis and often requires more aggressive therapies. Proper diagnosis of LC is essential because it can alter the appropriate treatment for a patient. S14 Journal of Investigative Dermatology (2016), Volume 136 075 Ephrin-A loss in cutaneous squamous cell carcinoma progression and metastasis J Zheng, B Perez White, N Kaplan, A Petty, Z Zhao, K Honda, M Denning, M Blumenberg, S Getsios and B Wang 1 Dermatology, Northwestern U., Chicago, IL, 2 Case Western Reserve U., Cleveland, OH, 3 Loyola U., Chicago, IL and 4 New York U., New York, NY Glycophosphatidylinositol-linked ephrin-A proteins target EphA receptor tyrosine kinases (RTKs) to promote keratinocyte differentiation and maintain tissue homeostasis. Accordingly, genetic ablation of EphA2, a major epidermal EphA subtype, increases susceptibility to chemically induced skin carcinogenesis in mice. Defining the corresponding role of ligands for EphA2 in skin cancer has been more cumbersome as the three ephrin-A genes (efna1, efna3, efna4) proximal to the epidermal differentiation complex gene cluster are each prominently expressed in skin. We met this challenge by engineering a triple efnA1/3/4 knock-out mouse (efnA-TKO mice) that reflects the pattern of reduced efnA gene expression found in mouse and human cutaneous SCCs. Skin tumors were evident earlier and grew faster in mice lacking these three ephrin-A ligands or EphA2. While histologically benign papillomas were prominent in EphA2-deficient mice, efnA-TKO mice developed invasive squamous cell carcinomas that metastasized to the lymph nodes and lungs within 25 weeks of DMBA-TPA treatment. Using primary mouse and human cell culture models, we found that ephrin-A proteins operate within the epidermis by targeting EphA2 to limit keratinocyte migration. We also illustrated a key tumor suppressive role for ephrin-A ligands in the surrounding tumor microenvironment by re-introducing isogenic tumor cell lines into the skin of wild-type or efnA-TKO mice. Importantly, the invasive phenotype of efnA-TKO mouse tumor cell lines was normalized by genetic reintroduction of efnA3. Integrating our findings from human tumors, mouse models, and primary cell cultures provides strong support for the notion that ephrins operate within tumor cells and also in the microenvironment to suppress skin cancer growth and metastasis. 076 Senescent fibroblasts enhance squamous cell carcinoma progression through secretion of Chemerin and activation of MAPK pathway V Farsam, A Basu, M Gatzka, M Wlaschek, N Treiber, MA Mulaw, T Lucas, S Kochanek and K Scharffetter-Kochanek 1 Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany, 2 Institute of Experimental Cancer Research, University of Ulm, Ulm, Germany and 3 Department of Gene Therapy, University of Ulm, Ulm, Germany Aging is associated with an increased risk of cutaneous squamous cell carcinoma (cSCC) partly due to the accumulation of mutations in stem/progenitor cells and partly due to the acquisition of a senescence-associated secretory phenotype (SASP) by senescent fibroblasts in dermal stroma. However, the mechanisms underlying the SASP-induced cSCC progression are not sufficiently understood. We investigated the SASP effect of senescent human dermal fibroblasts on cSCC cell motility in vitro using Transwell migration assay. Conditioned media (CM) of senescent fibroblasts significantly increased the migration of cSCC lines in comparison to young CM. Using RT-qPCR and specific ELISA, high levels of Chemerin transcripts and protein were found in senescent compared to young fibroblasts. An increase in Chemerin immunostaining in dermal fibroblasts of skin sections from old healthy individuals were observed as opposed to almost absent Chemerin immunostaining in young skin. Enhanced expression of Chemerin receptor CCRL2 was detected in cSCC lines when compared to normal keratinocytes. Increased CCRL2 was also confirmed with immunostaining of skin biopsies derived from patients suffering from cSCC. Recombinant human (rh) Chemerin enhanced the migration of cSCC lines in a concentration-dependent manner, while silencing Chemerin in senescent fibroblasts via siRNAs reduced cSCC migration. Chemerin was found to activate mitogen-activated protein kinase (MAPK) signaling pathway. Of note, inhibition of MAPK signaling pathway with chemical inhibitors impaired SASP-induced migration of cSCC cells in response to senescent fibroblast CM and rh Chemerin. In aggregate, these previously unreported data suggest that senescent fibroblasts may facilitate tumor progression through Chemerin-mediated activation of MAPK pathway in cSCC cells. 077 The role of intra-abdominal adipose tissue in UVB-induced skin cancer J Bernard and B Bullard Pharmacology and Toxicology, Michigan State University, East Lansing, MI Recent research suggests that a high-fat diet (HFD) and/or obesity (increased adiposity) are key players in the pathogenesis and prognosis of many common cancers. However the molecular changes induced by adipose tissue (AT) that actually enhance cancer development are poorly understood. Our previous studies indicated that decreasing visceral (intraabdominal) AT by surgical removal of the parametrial fat pads inhibited UVB-induced carcinogenesis in SKH-1 mice fed a HFD indicating that the parametrial AT from mice fed a HFD played a role in skin carcinogenesis. The purpose of this study was to investigate how a HFD may influence the intrinsic properties of the parametrial AT to induce UVB-induced skin tumor formation. We developed a system where molecules released and filtered from AT (fat tissue filtrate) stimulate JB6 P cell proliferation and transformation. The mouse BALB/c skin epithelial JB6 P cell line is a well-characterized model for neoplastic transformation that is responsive to tumor promoter-induced transformation growth in soft agar and is uniquely suited for studying tumor promotion and promotion-relevant molecular events in vitro. Our data demonstrate that fat tissue filtrate made from the parametrial ATof obese mice fed a HFD had 160% more transforming activity than that from mice fed a LFD (P |
