epidermal-growth-factor and Neoplasms--Germ-Cell-and-Embryonal

Testicular cancer is the most frequent cancer in young men aged 15-40 years and accounts for 1% of all cancer diagnosed in males. Testicular germ cell tumors (TGCT) encompass a broad group of cancers, each displaying different levels of pluripotency and differentiation as well as malignancy potential. The TGCT cell of origin is thought to be a fetal germ cell that failed to correctly differentiate during development: this is known as the ‘fetal origins hypothesis’. This theory predicts that developmental pathways that control germ cell pluripotency or differentiation may be involved in the malignant transformation of these cells. Recently the Nodal/Cripto signaling pathway, known to control pluripotency and differentiation in embryonic stem (ES) cells, was implicated in regulating normal male fetal germ cell pluripotency. Although genes of this pathway are not normally expressed in germ cells during adult life, ectopic expression of this pathway was detected in several sub-groups of TGCTs. In this review, we consider the evidence for the fetal origins of TGCT and discuss the implications of Nodal/Cripto signaling in various aspects of germ cell development and cancer progression.

Topics: Animals; Cell Differentiation; Epidermal Growth Factor; Fetus; Gene Expression Regulation, Developmental; Germ Cells; GPI-Linked Proteins; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Glycoproteins; Neoplasm Proteins; Neoplasms, Germ Cell and Embryonal; Nodal Protein; Signal Transduction; Testicular Neoplasms

Germ cells, the embryonic precursors of sperm or oocytes, respond to molecular cues that regulate their sex-specific development in the fetal gonads. In males in particular, the balance between continued proliferation and cell fate commitment is crucial: defects in proliferation result in insufficient spermatogonial stem cells for fertility, but escape from commitment and prolonged pluripotency can cause testicular germ cell tumors. However, the factors that regulate this balance remain unidentified. Here, we show that signaling by the TGFβ morphogen Nodal and its co-receptor Cripto is active during a crucial window of male germ cell development. The Nodal pathway is triggered when somatic signals, including FGF9, induce testicular germ cells to upregulate Cripto. Germ cells of mutant mice with compromised Nodal signaling showed premature differentiation, reduced pluripotency marker expression and a reduced ability to form embryonic germ (EG) cell colonies in vitro. Conversely, human testicular tumors showed upregulation of NODAL and CRIPTO that was proportional to invasiveness and to the number of malignant cells. Thus, Nodal signaling provides a molecular control mechanism that regulates male germ cell potency in normal development and testicular cancer.

Topics: Animals; Cell Differentiation; Cell Proliferation; Epidermal Growth Factor; Fibroblast Growth Factor 9; Germ Cells; Humans; Male; Membrane Glycoproteins; Mice; Neoplasm Proteins; Neoplasms, Germ Cell and Embryonal; Nodal Protein; Pluripotent Stem Cells; Signal Transduction; Spermatogenesis; Spermatogonia; Testicular Neoplasms; Testis; Transforming Growth Factor beta

Malignant germ-cell tumours arise from a neoplastic precursor, the carcinoma in situ, and develop into seminomas and/or non-seminomas (embryonal carcinomas, teratomas, yolk-sac tumours and choriocarcinomas). Based on histological and clinical findings, it has been postulated that seminomas can eventually transform into non-seminomas. Here, we used the cell line TCam-2 as model for seminomas and interrogated their differentiation potential. We demonstrate that TCam-2 cells are able to differentiate into mixed non-seminomatous lineages after supplementing the media with TGF-β1, EGF and FGF4. On a molecular level, the differentiation is initiated by repression of BMP/SMAD signalling. As a consequence, BLIMP1, a molecule known to inhibit the differentiation of murine primordial germ cells, is down-regulated and differentiation-inhibiting histone modifications are lost. The appearance of multinucleated giant cells and the expression of marker genes indicate that cells differentiate predominantly into extra-embryonic choriocarcinoma-like cells. This is most likely due to the presence of components of the Hippo pathway, TEAD4 and YAP1. These molecules have been described to trigger extra-embryonic fate determination in the murine system. This study supports the model that seminomas indeed have an intrinsic ability to transform into a non-seminoma. In addition, the data suggest that the transformation does not require an additional mutation, but can be triggered by changes in the tumour microenvironment.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone Morphogenetic Protein Receptors; Cell Differentiation; Cell Line, Tumor; Choriocarcinoma; DNA-Binding Proteins; Epidermal Growth Factor; Fibroblast Growth Factor 4; Giant Cells; Histones; Humans; Male; Muscle Proteins; Neoplasms, Germ Cell and Embryonal; Polymerase Chain Reaction; Positive Regulatory Domain I-Binding Factor 1; Repressor Proteins; Seminoma; Signal Transduction; Smad Proteins; TEA Domain Transcription Factors; Testicular Neoplasms; Transcription Factors; Transforming Growth Factor beta1; Tumor Microenvironment

Immunohistochemical distribution of human epidermal growth factor (hEGF) was described in 17 cases of mixed tumour of the skin with monoclonal antibody. In normal sweat glands, epithelial cells in the secretory portion and in the transitional area between secretory portion and duct showed prominent staining for hEGF. In the salivary pleomorphic adenoma type of mixed tumour of the skin, luminal tumour cells of tubular and duct-like structures gave a very characteristic hEGF staining reaction. The tumour cells showing strong staining for hEGF were scattered throughout the solid foci in this type of mixed tumour. Tubular epithelial cells in the clear cell adenoma type also displayed a positive hEGF reaction. And apocrine mixed tumours strong staining for hEGF occurred on the apical side of tubular and ductal tumour cells. In view of the immunohistochemical staining patterns for hEGF, the histologic origin of mixed tumours of the skin is suggested to be cells in the secretory portion and those in the transitional portion between secretory portion and duct of the sweat gland.

Topics: Adenoma, Pleomorphic; Antibodies, Monoclonal; Epidermal Growth Factor; Humans; Immunohistochemistry; In Vitro Techniques; Neoplasms, Germ Cell and Embryonal; Salivary Gland Neoplasms; Sweat Gland Neoplasms

The dexamethasone binding capacity of embryonal carcinoma cells and their differentiated derivatives was investigated. Manipulation of the embryonal carcinoma cell-culture conditions resulted in an unstable reversible expression of the glucocorticoid receptors. Stable expression of the receptors is observed when these cells are induced to differentiate. Cells grown under identical conditions were assayed for their ability to bind epidermal growth factor.

Topics: Animals; Cell Differentiation; Cell Line; Culture Media; Dexamethasone; Epidermal Growth Factor; Mice; Neoplasms, Germ Cell and Embryonal; Receptors, Glucocorticoid; Receptors, Steroid