Immunophenotypical analysis and immunobiology of childhood brain tumors

Cancer associated markers (CAMs) are the biochemical and immunological coun terparts of the morphology of neoplasms. The expression of an immunocytoche mically defined CAM is related to the tissue of origin and is not a random event. During the past two decades, the use of MoABs against oncofetal, neo plasm associated, cell lineage specific, endothelial, and cell proliferatio n related antigens in the diagnosis and biological assessment of prognosis in neoplastic disease gained increased importance. A sensitive direct corre lation exists between the expression of certain molecules and the developme nt of an inversive, highly malignant immunophenotype (IP) of neoplastic cel ls, allowing for the occurrence of angiogenesis and metastasis. Our systema tic and detailed cellular IP analyses of 82 childhood bm; rn tumors [34 med ulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs), 42 astrocyto mas (ASTRs), 5 choroid plexus papillomas (CPPs) and 1 choroid plexus carcin oma (CPC)] was conducted using over 55 MoABs. An indirect, Sour step, enzyme linked [alkaline phosphatase (AP) and peroxi dase (PO)], biotin-streptavidin based, antigen detection technique was empl oyed Our results allowed us to draw the following significant conclusions: 1) PNETs, ASTRs, CPPs, and CPCs display a heterogeneous IF; 2) both differe ntiated and immature neurofilament proteins are present in the great majori ty of childhood primary brain tumors; 3) gliomas, MEDs, and PNETs co-expres s GFAP, NF-H, NF-M, vimentin, and at least one cytokeratin; 4) neuronal dif ferentiation is always present within childhood brain tumors; 5) neoplastic ally 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 II molecules are not present on normal astrocytes in vivo, wher eas in vitro, in culture astrocytes express MHC class I and II molecules, e specially after interferon-gamma preincubation; 7) 65/76 PNETs and ASTRs co ntained armor infiltrating leukocytes (TIL), particularly the cytotoxic, MH C class I restricted and tumor associated antigen (TAA)-specific and direct ed CD8(+) lymphocyte clone, representing the functionally compromised effec tor cells of the host's cellula, immunological response; 8) granulocytes fi nd premyelocytes participate among the TIL, probably as a response to intra tumoral inflammation and necrotic changes; 9) the growth of solid neoplasms including childhood brain tumors even at clinically undetectable sires (a few mm(3) ), as well as the generation of an invasive cellular immunophenot ype (CIP) in neoplastic cells and distant metastases depends upon the conti nuous formation of new blood capillaries; 10) the newly organized tumor blo od capillaries' most striking feature is the presence of markedly enlarged and disorganized perivascular spaces, measuring at least 2-5 mm, detected i n all observed childhood primary brain tumors and 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 immunomorphologic ally by the detection of endoglin (EDG/CD105), a transforming growth factor -beta (TGF-beta) receptor and a proliferation-associated antigen (PAA) expr essed on endothelial cell surfaces; 12) inhibition of angiogenesis as a for m of anti-neoplastic therapy has been and should be extensively studied; 13 ) brain armor cells often express ess an apoptosis related transmembrane gl ycoprotein Fas/APO-1 (CD95), member of the nerve growth factor/tumor necros is receptor superfamily which is not present on normal cells in the CNS, ap optosis being triggered by the binding of Fas/APO-1 to its natural ligand ( Fas-L/APO-1L); 14) further studies should substantiate the importance of CD 105 ol EDG in the earliest possible detection diagnosis and neoplasm relate d angiogenesis inhibition-based treatment of mammalian solid neoplasms, esp ecially childhood brain tumors; 15) future observations of tumor immunobiol ogy, cell cycle regulation and endothelial cell proliferation should aid in the development of individualized, fourth modality immunotherapeutical reg imens for primary childhood brain tumors.