Cancer associated markers represent the biochemical or immunological counterparts of the morphology of tumors. The expression of an immunocytochemically defined cancer associated marker is also related to the tissue of origin and is not a random event. During the past two decades, the use of MoABs against oncofetal, neoplasm associated, cell lineage specific, endothelial, and cell proliferation related antigens in the diagnosis and biological assessment of prognosis in neoplastic disease gained increased importance. A sensitive direct correlation exists between the expression of certain molecules and the development of an invasive, highly malignant immunophenotype (IP) of neoplastic cells, accompanied by pathobiological events such as angiogenesis and metastasis. Our systematic and detailed cellular IP analyses of 82 childhood brain humors [34 medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs), 42 astrocytomas (ASTRs), 5 choroid plexus papillomas (CPPs) and 1 choroid plexus carcinoma (CPC)], was conducted using over 55 MoABs. An indirect, four-step, enzyme linked [alkaline phosphatase (AP) and peroxidase], biotin-streptavidin based, antigen detection technique was employed. Our results allowed us to draw the following significant conclusions: (1) PNETs, ASTRs, CPPs, and CPCs display a heterogeneous IF; (2) both differentiated and immature neurofilament proteins are present in the great majority of childhood primary brain tumors; (3) gliomas, MEDs, and PNETs co-express GFAP, NF-H, NF-M, vimentin, and at least one cytokeratin; (4) neuronal differentiation is always present within childhood brain tumors; (5) neoplastically transformed astrocytes may be able to present antigens to infiltrating T lymphocytes since MHC molecules are expressed on their surfaces; (6) MHC class I and Il molecules are not present on normal astrocytes in vivo, whereas in vitro cultured astrocytes express MHC class I and II molecules, especially after interferon-gamma preincubation; (7) 65/76 PNETs and ASTRs contained tumor infiltrating leukocytes (TIL), particularly the cytotoxic, MHC class I-restricted and tumor associated antigen (TAA)-specific and directed, CD8(+) lymphocyte clone, representing the functionally compromised effector cells of the host's cellular immunological response; (8) granulocytes and premyelocytes participate among the TIL, probably as a response to intratumoral inflammation and necrotic changes; (9) the growth of solid neoplasms, including childhood brain tumors, even at clinically undetectable sizes (a few mm(3)), as well as the generation of an invasive cellular immunophenotype (CIP) in neoplastic cells and distant metastases depends upon the continuous formation of new blood capillaries; (10) the newly organized tumor blood capillaries' most striking feature is the presence of markedly enlarged and disorganized perivascular spaces, measuring at least 2-5mm, detected in all observed childhood primary brain tumors and was independent of the tumor's size, as well as its morphological and cellular differentiation features; (11) endothelial cells undergo rapid proliferation during neoplasm related and induced neo-vascularization which can be demonstrated immunomorphologically by the detection of the cell surface localized endoglin (EDG/CD105), a transforming growth factor-beta (TGF-beta) receptor and a proliferation-associated antigen (PAA) expressed on endothelial cell surfaces; (12) inhibition of angiogenesis as a form of anti-neoplastic therapy has been and should be extensively studied; (13) brain tumor cells often express an apoptosis related transmembrane glycoprotein Fas/APO-l (CD95), a member of the nerve growth factor/tumor necrosis receptor superfamily, which is not present on normal cells in the CNS (apoptosis being trigerred by the binding of Fas/APO-1 to its natural ligand (Fas-L/APO-1L)); (14) further studies should substantiate the importance of CD105 or EDG in the earliest possible detection, diagnosis and neoplasm related angiogenesis inhibition-based treatment of mammalian solid neoplasms, especially childhood brain tumors; (15) future observations of immunobiology, cell cycle regulation and endothelial cell proliferation should aid in the development of individualized, fourth modality, immunotherapeutical regimens for primary childhood brain tumors.
