Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation.

Lefty is a member of transforming growth factor-beta (TGF-β) superfamily and a potent antagonist of the TGF-β/Nodal/Activin signaling pathway. Lefty is critical in sustaining self-renewal/pluripotency status, and implicated in the differentiation of embryonic stem cells (ESCs). However, emerging studies depict Lefty as a multifaceted protein involved in myriad cellular events.

Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi.

Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma.

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment.

Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/adjuvant chemotherapy. To better understand the growth advantage of TNBC - in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers.

Effects of a novel Nodal-targeting monoclonal antibody in melanoma.

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation.

Divergence(s) in nodal signaling between aggressive melanoma and embryonic stem cells.

The significant role of the embryonic morphogen Nodal in maintaining the pluripotency of embryonic stem cells is well documented. Interestingly, the recent discovery of Nodal's re-expression in several aggressive and metastatic cancers has highlighted its critical role in self renewal and maintenance of the stem cell-like characteristics of tumor cells, such as melanoma. However, the key TGFβ/Nodal signaling component(s) governing Nodal's effects in metastatic melanoma remain mostly unknown.

Nodal signaling promotes a tumorigenic phenotype in human breast cancer.

The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined.

Melanoma tumor cell heterogeneity: a molecular approach to study subpopulations expressing the embryonic morphogen nodal.

As the frequency of melanoma increases, current treatment strategies are struggling to significantly impact patient survival. One of the critical issues in designing efficient therapies is understanding the composition of heterogeneous melanoma tumors in order to target cancer stem cells (CSCs) and drug-resistant subpopulations. In this review, we summarize recent findings pertinent to the reemergence of the embryonic Nodal signaling pathway in melanoma and its significance as a prognostic biomarker and therapeutic target.

The significance of a Cripto-1 positive subpopulation of human melanoma cells exhibiting stem cell-like characteristics.

Cripto-1 (CR-1) protein function differs according to cellular or extracellular expression. In this study, we explore the significance of cell surface CR-1 expression in human melanoma cells. Cell surface CR-1-expressing human melanoma cells (CR1-CS+) were selected by fluorescence-activated cell sorting (FACS) and grown in vitro and in vivo in nude mice to study their growth characteristics.