Dermal Melanoma Research Articles

Tumor response and patient survival after intralesional therapy with low-dose GM-CSF and IL-2 in metastatic and primary cutaneous melanoma: An exploratory study.

e20002 Background: Dermal and subdermal metastatic melanoma can give us an excellent opportunity to evaluate the local and systemic effects of intralesional therapy. While GM-CSF administration can...

Sequential Intralesional Administration of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) in Dermal and Subdermal Melanoma Lesions Can Induce Immense Antitumor Immune Response: A Potential New Approach to Adjuvant Immunotherapy

Sequential Intralesional Administration of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) in Dermal and Subdermal Melanoma Lesions Can Induce Immense Antitumor Immune Response: A Potential New Approach to Adjuvant Immunotherapy

E- to N-cadherin switch in melanoma is associated with decreased expression of phosphatase and tensin homolog and cancer progression

Cadherin switch in melanoma, with loss of E-cadherin and upregulation of N-cadherin, is believed to underlie melanoma cell detachment from the epidermis and promotion of dermal and vascular melanoma invasion. The tumour suppressor phosphatase and tensin homolog (PTEN) has been suggested as a potential regulator of this cadherin switch. To study the biological and clinical implications of cadherin switch and PTEN expression in melanoma progression. We constructed tissue microarrays from primary tumour samples from 394 formalin-fixed paraffin-embedded melanomas diagnosed between 2001 and 2006. Median follow-up was 10 years. Tissue microarray sections were stained by immunohistochemistry for E-cadherin, N-cadherin and PTEN, and expression was analysed semiquantitatively. Breslow thickness correlated strongly with reduced/absent PTEN expression (P < 0·0001), low E-cadherin expression (P < 0·0001), high N-cadherin expression (P < 0·0001) and the combination of low E-cadherin and high N-cadherin expression (cadherin switch profile; P = 0·001). There was a significant association between reduced/absent PTEN and the presence of the cadherin switch profile (P = 0·03). In univariate analyses, low E-cadherin expression significantly predicted an adverse overall relapse-free (P = 0·04), melanoma-specific (P = 0·03) and distant-metastasis-free (P = 0·01) survival; reduced/absent PTEN predicted an adverse overall relapse-free survival (P = 0·006), and the cadherin switch profile predicted adverse melanoma-specific (P = 0·005) and distant-metastasis-free (P = 0·01) survival. In multivariate analysis, the cadherin switch profile was an independent prognostic marker of melanoma-specific (P = 0·04) and distant-metastasis-free survival (P = 0·02). Cadherin switch and reduced/absent PTEN expression are associated in melanoma, and both factors may play important roles in the progression of melanoma.

Primary Dermal Melanoma: A Case Report and a Review of the Literature

Patients with cutaneous metastatic melanoma of unknown primary origin (stage IV M1a disease according to the American Joint Committee on Cancer melanoma staging system) have an estimated 5-year survival rate of between 5% and 17.9% and a median survival of 6 months. However, certain patients with stage IV M1a disease have much higher survival rates. The existence of this subpopulation has given rise to the term primary dermal melanoma to describe such cases.We report a case of melanoma with characteristics consistent with primary dermal melanoma and review the relevant literature. A diagnosis of primary dermal melanoma requires careful clinical and pathologic correlation and should be considered in all patients with a solitary melanoma confined to the dermis and subcutaneous tissue when there is no evidence of a primary tumor or disease at other sites following appropriate staging studies. We believe that familiarity with this subtype of melanoma is essential in order to provide patients with optimal care and better prognostic information.

Primary Dermal Melanoma in a 19-Year-Old Asian Man

Primary dermal melanoma (PDM) is a distinct subtype of solitary dermal melanoma (SDM) defined as a dermal malignancy confined to the dermis or subcutaneous tissues without an epidermal component and other primary melanomas. It is rarely reported in the literature and has a low incidence rate (<1%) in the population with melanoma and an apparently excellent prognosis. In the Asian population, the incidence is even lower; only one Japanese woman has ever been reported. We report a young Taiwanese man with PDM and review the possible pathogenesis.

Abstract A36: Treatment of established dermal murine B16F10 melanoma with an attenuated Toxoplasma gondii eliminates the treated tumor and stimulates systemic antitumor immunity.

Abstract While the surgical removal of dermal melanoma cures that lesion, it does nothing to stimulate antitumor immunity that could potentially identify and eliminate occult metastatic disease. An immune based treatment that eliminates the primary dermal melanoma could also potentially generate systemic immunity that will protect against metastatic disease. We have utilized an attenuated strain of Toxoplasma gondii (cps) to break tumor-mediated immunosuppression, stimulate an antitumor immune response that eliminates the dermal tumor, and generate systemic antitumor immunity that leads to rejection of subsequent dermal or intravenous challenges with B16F10. T. gondii is an obligate intracellular eukaryotic parasite that infects virtually any mammalian species. The cps strain is a uracil auxotroph that can be grown in vitro but is unable to replicate in vivo. Despite its lack of infectivity, it enters cells and stimulates a strong T-cell mediated immune response characterized by long lasted CD8 effector cells. The presence of cps in the tumor microenvironment modifies the phenotype of tumor infiltrating leukocytes, and along with the expected anti-Toxoplasma immune response there is antigen-spreading so that tumor antigens are responded to and the immune system recognizes subsequent tumor challenges when there is no associated cps. The treatment requires CD8 and NK cells for efficacy but does not require CD4 cells. The treatment also requires that the host express IL-12 and Ifn-g. The treatment requires live cps for efficacy and is effective in mice that are latently infected with another strain of T. gondii, so it could function in the high percentage of humans with latent T. gondii infection and an established immune response against T. gondii. Citation Format: Steven Fiering, Jason R. Baird, Katelyn Byrne, Patrick Lizotte, David Mullins, Mary Jo turk. Treatment of established dermal murine B16F10 melanoma with an attenuated Toxoplasma gondii eliminates the treated tumor and stimulates systemic antitumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A36.

前額部に生じたPrimary dermal melanomaの1例

65歳，女性。数十年前から存在した右眉毛上部の色素斑に1年前より皮下腫瘤が出現し，増大してきたため近医形成外科を受診した。粉瘤疑いで切除されたが，病理組織検査で悪性黒色腫と診断され，当科紹介受診となった。前医での切除標本病理組織像では，真皮から皮下にメラニン色素を有する異型細胞の増殖を認めたが，表皮内に異型メラノサイトはみられずprimary dermal melanomaと診断した。初診時には右眉毛上部の手術瘢痕から耳下腺部までの皮下に硬く腫大した腫瘤が列序性に多発していた。これらの腫瘤を一塊とした腫瘍切除術と全層植皮術および頸部リンパ節郭清術を行った。皮下の腫瘤はin－transit転移であり，耳下腺内リンパ節にも転移が認められたことからprimary dermal melanoma，pTN3M0，stage IIIcと診断した。術後にDAV－Feron療法6クールを行い，INF－β局注を追加し加療したが，術後1年3ヵ月で小腸に悪性黒色腫の転移が出現したため，翌月に外科にて小腸切除術を行った。初療開始後2年3ヵ月，小腸転移切除後9ヵ月が経過しているが新たな再発・転移は認めていない。

DIAGNOSIS AND TREATMENT OF A DERMAL MALIGNANT MELANOMA IN AN AFRICAN LION (PANTHERA LEO)

A 13-yr-old intact male African lion (Panthera leo) presented with a 4-mo history of left maxillary lip swelling. On physical examination, a 10-cm-diameter, ulcerated, round, firm, and pigmented mass at the level of the left maxillary canine tooth was noticed. All other organ systems examined were within normal limits. Multiple biopsies of the mass were collected and fixed in 10% neutral buffered formalin. Histopathologic evaluation of the biopsies revealed a malignant dermal melanoma. Hematologic and plasma biochemical parameters were within normal reference ranges. Thoracic radiographs taken 3 days following initial presentation showed no evidence of metastasis of the tumor. Computed tomography of the skull and neck was performed to evaluate local tumor invasion and to plan for hypofractionated radiation therapy. Therapy included four weekly treatments of 8 gray external-beam hypofractionated radiation and four bimonthly immunotherapy treatments. Following this treatment regime, the tumor size was reduced by 50%, and surgical excision was performed. No major side effects associated with radiation or immunotherapy were seen. Six months after diagnosis, hematologic and plasma biochemical parameters were within normal limits, thoracic radiographs showed no evidence of metastasis, and the lion showed no clinical signs of disease. The lion will continue to receive immunotherapy every 6 mo for the rest of its life. To the authors' knowledge, this is the first report of a successful treatment of a malignant dermal melanoma with external-beam hypofractionated radiation, immunotherapy, and surgical excision in an African lion.

Primary Dermal Melanoma Latent for More than 10 Years

Dear Editor: Primary dermal melanoma (PDM) has been described as a novel rare variant of melanoma that is confined to the dermis and/or subcutaneous tissue1,2. There have been no reports focusing on the duration of PDM so far. We report here a case of PDM for more than 10 years. A 54-year-old Japanese woman was presented with an asymptomatic nodule on her sacral region. It had been present for more than 10 years. Two years later, she visited us again, complaining that the lesion had been growing and was painful for the past two months. A physical examination revealed a brown/red, elastic hard, dome-shaped nodule measuring 18×18 mm in diameter (Fig. 1A). A histopathological examination revealed a solitary, well-circumscribed, dermal and subcutaneous nodule that was encapsulated by fibrous tissue with extensive central necrosis and hemorrhage (Fig. 1B). Immunohistochemistry (IHC) showed that the tumor cells were positive for S100 protein, Melan-A and HMB-45 (Fig. 2A). In addition, IHC for p53, cyclin D1 and Ki-67 (Fig. 2B) were low positive (8.0%, 14.7% and 14.9% of cells were positive, respectively). Moreover, negative staining for D2-40 was observed. Positron emission tomography and computed tomography revealed no evidence of another primary melanoma or metastatic lesions. We diagnosed her with PDM. Wide local excision with a 2 cm margin was performed again. Then, the patient received a course of DAV-feron therapy (dacarbazine, nimustine hydrochloride, vincristin sulfate and interferon-β), followed by several local injections of interferon-β. After 3 years of follow-up, there has been no evidence of recurrence or metastasis. Fig. 1 (A) Brown/red nodule on the sacral region. (B) Primary dermal melanoma composed of a dermal and subcutaneous nodule surrounded by fibrous tissue, with extensive central necrosis and hemorrhaging (H&E, ×10). Fig. 2 Immunohistochemical findings of primary dermal melanoma. (A) HMB-45 staining was focally positive (×200). (B) Ki-67 staining was low positive (14.9% of cells were positive) (×200). Clinically, PDM may be misdiagnosed due to its features, which resemble a cyst or subcutaneous nodule. Histopathologically, it is difficult to differentiate PDM from solitary cutaneous metastatic melanoma. Recently, low levels of p53, Ki-67, cyclin D1 and D2-40 unique to PDM have been proposed2. Our findings were concordant with them. Central necrosis and hemorrhage were seen in our case. Of course these features may be the reflection of traumatized melanocytic nevus; moreover, these features are also frequently observed in PDM2. Furthermore, characteristic changes indicative of traumatized melanocytic nevus, such as ulceration, parakeratosis and less than 5% of Ki-67 labeling, were not recognized in our case. According to the 2009 American Joint Committee on Cancer (AJCC) melanoma staging guidelines, localized metastases to the skin or subcutaneous tissues with an unknown primary site are defined as stage III, although they are classified as stage IV (M1a) according to the 2002 AJCC melanoma staging database3. The five-year survival rate of stage IIIB (T1-4aN2cM0) melanoma is 59%3. In contrast, the Kaplan-Meier 8-year survival rate of PDM was 83% in one series1 and 92% at a mean follow-up duration of 44 months in another2. Thus, patients with PDM achieve markedly better survival compared to metastatic melanoma patients. Although we cannot deny the possibility of recent malignant changes from the preexisting melanocytic dermal nevus, it is worth noting that our case has more than 10 years of history. The disease duration of PDM was not mentioned in the previous 2 case series1,2. One Japanese case showed a 3-year history4. Long disease duration may be indicative of less aggressive behavior.

Melanoma dérmico primario: presentación de un caso y revisión de la literatura

Patients with cutaneous metastatic melanoma of unknown primary origin (stage IV M1a disease according to the American Joint Committee on Cancer melanoma staging system) have an estimated 5-year survival rate of between 5% and 17.9% and a median survival of 6 months. However, certain patients with stage IV M1a disease have much higher survival rates. The existence of this subpopulation has given rise to the term primary dermal melanoma to describe such cases.We report a case of melanoma with characteristics consistent with primary dermal melanoma and review the relevant literature. A diagnosis of primary dermal melanoma requires careful clinical and pathologic correlation and should be considered in all patients with a solitary melanoma confined to the dermis and subcutaneous tissue when there is no evidence of a primary tumor or disease at other sites following appropriate staging studies. We believe that familiarity with this subtype of melanoma is essential in order to provide patients with optimal care and better prognostic information.

A blueprint for staging of murine melanocytic lesions based on the Cdk4R24C/R24C::Tyr‐NRASQ61K model

It has been shown that gene mutations which drive the development of malignant melanoma (MM) in humans also lead to emergence of MM when engineered mice. However, little attention has been paid to the clinical and histopathological features of melanocytic lesions and their natural history in a given mouse model. This knowledge is crucial to enable us to understand how engineered mutations influence the initiation and evolution of melanocytic lesions, and/or for the use of mice as a preclinical model to test specific treatments. We recently reported the development of melanocytic proliferations along the spectrum of naevi to MM in a Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) mouse model. In this study, we followed the development of lesions over time using digital photography and dermoscopy with the aim to correlate the clinical and histopathological features of lesions developing in this model. We identified two types of lesions. The first are slow-growing dermal MMs that emanate from dermal naevi. The second did not emanate from naevi, grew rapidly, and appeared to be solely confined to the subcutaneous fat. We present a simple staging system for the MMs that progress from naevi, based on depth of extension into the dermis and subcutis. This represents a blueprint for documentation and follow-up of MMs in the live animal, which is critical for the proper use of murine melanoma models.

Diagnosis of blue nevus-like metastatic uveal melanoma confirmed by fluorescence in situ hybridization (FISH) for monosomy 3

Metastatic melanoma can on rare occasion simulate the appearance of a blue nevus clinically and/or histopathologically, which may lead to diagnostic confusion and delay in treatment. Given the known difficulty in recognizing a small dermal blue nevus-like melanoma metastasis by light microscopic findings alone, recent discoveries of unique cytogenetic aberrations in various types of melanomas have led pathologists to explore cytogenetic techniques as an ancillary diagnostic tool. Herein, we report a case of a 58-year-old man with a history of uveal melanoma, in which fluorescence in situ hybridization (FISH) analysis for monosomy 3 helped confirm a diagnosis of blue nevus-like uveal melanoma metastasis. The patient had presented clinically with a new small 1-mm dark blue-gray macule on the forehead. Histopathologically, a small dermal nodule of pigmented epithelioid melanocytes and melanophages was found with a rare mitotic figure. The pathologist's suspicion of a blue nevus-like melanoma metastasis was confirmed by FISH analysis: both the tumor cells of the patient's prior uveal melanoma and the melanocytes of the new dermal blue nevus-like nodule carried only one copy of chromosome 3. Furthermore, deletion of 1p36 and amplifications of 8q32 were also identified.

Nickel, copper, and zinc centered ruthenium-substituted porphyrins: effect of transition metals on photoinduced DNA cleavage and photoinduced melanoma cell toxicity

Coordination of two [Ru(bipy)(2)Cl](+) moieties (where bipy = 2,2'-bipyridine) to the pyridyl nitrogens in the 5,10-positions of meso-5,10,15-(4-pyridyl)-20-(pentafluorophenyl)porphyrin gives the diruthenium porphyrin complex I. Insertion of nickel(II), copper(II), and zinc(II) into the porphyrin center gives the complexes II-IV, respectively. Electronic transitions associated with the ruthenium porphyrin include an intense Soret band and four less intense Q-bands in the visible region of the spectrum. An intense π-π* transition in the UV region associated with the bipyridyl groups and a metal-to-ligand charge transfer (MLCT) band appearing as a shoulder to the Soret band are also observed. A shift of the Soret band and collapse of the Q-bands into one band is observed upon insertion of the metal ions into the porphyrin center. Electrochemical properties associated with the complexes include a redox couple in the cathodic region attributed to the porphyrin and a redox couple in the anodic region due to the Ru(III/II) couple. DNA titrations of the complexes indicate that they interact strongly with DNA potentially through an intercalation mechanism. Irradiation of aqueous solutions of the complexes and supercoiled DNA at a 5:1 base pair to complex ratio with visible light above 400 nm shows nicking of DNA for the nickel(II) and copper(II) complexes and photocleavage of DNA for the zinc(II) complex. Cell studies with dermal skin (normal) fibroblast and melanoma cells indicate that the free base porphyrin(I) is toxic to both normal and melanoma cells, while the nickel(II) and copper(II) complexes, II and III, are non-toxic to both cell lines when irradiated with a tungsten lamp. The zinc(II) complex, IV, is non-toxic to normal cells but toxic to melanoma cells when irradiated under the same conditions.

Primary Dermal Melanoma の1例

Primary Dermal Melanoma の1例

Ancient Melanocytic Nevus: A Simulator of Malignant Melanoma

Ancient melanocytic nevus (AN) is an unusual but distinctive melanocytic neoplasm within the spectrum of simulators of malignant melanoma. This report describes 13 patients with AN where a long follow-up information was available. Histopathology is characterized by 2 populations of melanocytes, namely, one with large pleomorphic cells and the other with small melanocytes. A few mitotic figures may be present exceptionally. MIB-1 (Ki67) proliferation marker reveals an overall low nuclear labeling index. Additional important findings are stromal degenerative changes. AN must be especially differentiated from dermal melanoma arising in a nevus.

Melanoma in the Skin of a Nurse Shark (Ginglymostoma cirratum)

A female nurse shark, Ginglymostoma cirratum, estimated at 27 yr of age had a 5.5-yr history of a 6-cm black, raised nodular skin lesion located on the right side of the proximal tail. The lesion was diagnosed on biopsy as a slow-growing melanoma of the skin with no vascular invasion. The nurse shark was euthanized for systemic illness approximately 4.5 mo after diagnosis of the dermal melanoma. No evidence of metastasis was found on histopathologic evaluation of the skin and viscera.

P125. PAX3 enhances response to environmental stimuli in normal skin melanocytes and melanocytic lesions

Cutaneous malignant melanoma is an aggressive form of skin cancer, arising in cutaneous melanocytes. The transcription factor PAX3 regulates melanocyte specification from neural crest cells during development but expression in differentiated melanocytes is uncertain. By contrast it is frequently found in melanomas and naevi and is a marker for melanoma staging and detection. In this study we analysed the expression of PAX3 across the spectrum of melanocytic cells, from normal melanocytes to cells of benign and malignant lesions to better assess its function in these various tissues. PAX3 expression was analysed by immunohistochemistry and qRT-PCR. Immunofluorescence was used for co-expression with differentiation, migration and survival markers. As expected PAX3 expression was observed in naevi and melanoma cells. It was also found in melanocytes of normal skin where it coexpressed with melanocyte markers, MITF and MLANA. Co-expression with its downstream target, antiapoptotic factor BCL2L1 confirms PAX3 as a cell survival regulator. PAX3 was also co-expressed with melanoma cell migration marker MCAM in dermal naevi and melanoma cell nests, but this downstream target of PAX3 was not present in normal epidermal melanocytes, suggesting differential roles for PAX3 in normal epidermal melanocytes and melanoma cells. Most interestingly, a proportion of PAX3-positive epidermal melanocytes in normal skin show HES1 and Ki67 co-expression, indicating their less differentiated proliferative phenotype. Our results suggest that a previously identified role for PAX3, that of regulator of an undifferentiated plastic state, may operate in melanocytes of normal skin. This role, possibly required for cellular response to environmental stimuli, may contribute to formation and development of melanocytic lesions in which PAX3 expression is prominent.

The role of radiotherapy in the palliation of cutaneous melanoma metastases: A case series of 3 patients

The prevalence of melanoma in Australasia is 37.7 per 100,000 in men and 29.4 per 100,000 in women. Although the primary modality for treatment remains surgical, adjuvant therapies such as radiotherapy are often called into use for palliation in stage IV disease. The treatment of disseminated dermal deposits presents a particular challenge for which we have had a very favourable response with the use of brachytherapy or high dose radiation (HDR). Waikato Hospital in New Zealand offers brachytherapy to palliative patients as an option to control cutaneous metastases. This case series consists of three patients who underwent treatment with brachytherapy for cutaneous metastases delivered by surface moulds. No further recurrence in any of our patients with a maximum time of 21 months. We would advocate the use of brachytherapy in certain clinical situations as a useful palliative treatment for disseminated dermal melanoma metastases which are otherwise very difficult to control.

PAX3 Expression in Normal Skin Melanocytes and Melanocytic Lesions (Naevi and Melanomas)

BackgroundCutaneous Malignant Melanoma is an aggressive form of skin cancer, arising in cutaneous melanocytes. The transcription factor PAX3 regulates melanocyte specification from neural crest cells during development but expression in differentiated melanocytes is uncertain. By contrast it is frequently found in melanomas and naevi and is a marker for melanoma staging and detection. In this study we analysed the expression of PAX3 across the spectrum of melanocytic cells, from normal melanocytes to cells of benign and malignant lesions to better assess its function in these various tissues. Pax3 and PAX3 (italicized) refer to the mouse and human gene, respectively; whereas Pax3 and PAX3 (non-italicized) refer to the corresponding mouse and human protein.Methodology and Principal FindingsPAX3 expression was analysed by immunohistochemistry and qRT-PCR. Immunofluorescence was used for co-expression with differentiation, migration and survival markers. As expected PAX3 expression was observed in naevi and melanoma cells. It was also found in melanocytes of normal skin where it co-expressed with melanocyte markers, MITF and MLANA. Co-expression with its downstream target, antiapoptotic factor BCL2L1 confirms PAX3 as a cell survival regulator. PAX3 was also co-expressed with melanoma cell migration marker MCAM in dermal naevi and melanoma cell nests, but this downstream target of PAX3 was not present in normal epidermal melanocytes, suggesting differential roles for PAX3 in normal epidermal melanocytes and melanoma cells. Most interestingly, a proportion of PAX3-positive epidermal melanocytes in normal skin show HES1 and Ki67 co-expression, indicating their less differentiated proliferative phenotype.Conclusions and SignificanceOur results suggest that a previously identified role for PAX3, that of regulator of an undifferentiated plastic state, may operate in melanocytes of normal skin. This role, possibly required for cellular response to environmental stimuli, may contribute to formation and development of melanocytic lesions in which PAX3 expression is prominent.

Abstract 3299: Expression of exchange protein activated by cAMP (Epac) in melanoma and its role in cell migration

Abstract Background: We previously reported that Epac, a guanine nucleotide exchange factor directly activated by cAMP, increases cell migration in melanoma. Epac1, a major isoform of Epac, increases melanoma cell migration via production of heparan sulfate (HS), a major extracellular glycosaminoglycan. However, the frequency and level of expression of Epac1 in human melanoma tissues is largely unknown. Furthermore, it is still unclear if Epac1's role in heparan sulfate production and cell migration is universal among different melanomas. Methods: Epac1 mRNA expression was examined in melanoma cell lines at different melanoma progression stages, and in human fresh frozen tissue of four different stages, i.e., primary melanoma, regional dermal metastatic melanoma, lymph node metastatic melanoma and distant metastatic melanoma. Also, melanoma and melanocyte cell lines were subjected to cell migration assay with the Boyden chambers. Epac1 expression was ablated by shRNA to examine involvement of Epac1 in cell migration and HS production. Results: There was a tendency toward higher Epac1 mRNA expression with progression of melanoma stage, i.e., Epac1 mRNA was higher in metastatic melanoma (MM) and vertical growth phase (VGP) melanoma cell lines than in a melanocyte cell line. In human melanoma samples, Epac1 mRNA expression was higher in regional dermal (p=0.04, n=10) and lymph node (p=0.03, n=10) metastatic melanoma than in primary melanoma, but not in distant metastatic melanoma; however, 4 out of 10 distant metastatic melanoma showed more than 2-fold increase of Epac1 mRNA expression compared to primary melanoma. These data suggest that Epac1 expression correlates with melanoma stage. When cells were incubated with 8-pMeOPT-2′-O-Me-cAMP, an Epac-specific agonist, cell migration was increased in melanoma cell lines but not in melanocytes. Heparatinase, a heparan sulfate-degrading enzyme, inhibited 8-pMeOPT-2′-O-Me-cAMP-induced cell migration in 2 metastatic melanoma cell lines, SK-Mel-2 (64.6±7.5 vs. 35.2±5.5 cells/field, p&amp;lt;0.05, n=4) and SK-Mel-187 (70.2±6.6 vs 43.2±9 cells/field, p&amp;lt;0.05, n=4) in parallel with decreased HS production. When Epac1 expression was ablated by shRNA, cell migration was decreased (SK-Mel-2, 92.6±4 vs. 49.3±1 cells/field, p&amp;lt;0.05, n=4; SK-Mel-187, 77.9±9 vs. 31.6±5 cells/field, p&amp;lt;0.05, n=4) in parallel with decreased HS production (SK-Mel-2,13 vs. 6.8±0.6 μg/ml, p&amp;lt;0.05, n=4; SK-Mel-187, 46.6±6.2 vs. 26.1±8.2 μg/ml, p&amp;lt;0.05, n=4). These data suggest that Epac1 expression plays a major role in melanoma cell migration through heparan sulfate production, and Epac's role is universal in metastatic melanoma cells. Conclusion: Epac1 expression increases with the progression of melanoma. Epac1 mediates melanoma cell migration via HS production in different melanoma cell lines. These data suggest that Epac1 could be a target for treating patients with melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3299.