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I have previously assumed that in tumours there are stem cells, that owing to the morphophysiologic properties shared with embryonal cells I have defined as 'para-embryonal' cells (PECs). Owing to a blocking mutation, PECs might be able to express only the genic program upstream from the block, but not that downstream. As a consequence, PECs might lack in genic differentiated products, such as MHC molecules, and might be very rich in primitive genic products, such as HSP70 molecules. Like embryonal cells, PECs might carry out induction on adjoining hyperplastic cells, thus transforming them, only phenotypically, into 'differentiated para-embryonal cells' (DPECs), endowed with both MHC and HSP70 molecules. In such a way, nuclei of MHC-non-expressing/HSP70-high expressing stem tumour cells might be surrounded by layers of MHC-expressing/HSP70-expressing non-stem tumour cells. Such a structural tumour organization, actually found by C. Cordon Cardo et al. with regard to the MHC molecule expression, might be responsible for interference phenomena versus the MHC-non-restricted immune cells, such as macrophages and NK cells. So, these cells, the only potentially able to recognize and eliminate MHC-non-expressing stem tumour cells (PECs), might spare them, thus rendering cancer a biological process without any natural immunological solution. Now, I would like to theorically demonstrate that cancer might be a process without immunological solution from the very beginning: the first stem tumour cell might be tolerated as a sort of 'primordial self' because of its MHC-null/HSP70-very high phenotype, recognizable by neither the MHC-restricted nor the MHC-non-restricted immunesurveillance systems of the host. Possible biological roles of HSP70 molecules might account for the immunesurveillance escape of stem tumour cells. Existence of these cells appears to be confirmed by the recent experiments of immunotherapy with autologous tumour-specific HSPs carried out by P. K. Srivastava; moreover, their 'self' nature appears to be confirmed by the most recent experiments of compatible bone marrow allograft carried out by A. M. Carella. On this ground, the main steps for a resolutive antitumour immunotherapy are proposed., (Copyright 2001 Harcourt Publishers Ltd.)

The close association of heat shock protein (HSP), haemopoietic histocompatibility (Hh), major histocompatibility complex (MHC), and complement genes on the same chromosomal region, and the fact that all these genes are inherited on the whole in each haplotype of an individual, might indicate some evolutionary and functional correlations among them. Several data suggest for HSP70 molecules a possible role as a molecular target recognizable by natural killer (NK) cells. HSP70 sequences from both prokaryotic and eukaryotic organisms reveal that about half of the amino acid residues are identical and many of the remaining residues are similar. I here assume that NK reactivity might start, early in the immunogenesis process, as a effect of the interaction between HSP70 molecules and a hypothetical HSP receptor of yet immature non-cytolytic NK cells. To this receptor, an HSP molecule might act as an activator or an inhibitor depending on whether its amino acid residues are reactive or not with it, respectively. Later in the immunogenesis process, murine Hh or human equivalent molecules, dominantly expressed in bone marrow target cells, might select the non-reactive NK clones of an individual, inducing them to mature and express a lytic machinery. As a consequence of the NK maturation, proliferating hemopoietic target cells expressing only or mainly activator HSPs on their surface might undergo NK cytolysis. This might explain the NK lysis of apparently normal cells found in human foetal marrow; moreover, this might explain in some way the F1 hybrid resistance phenomenon. The NK reactivity of an individual would be further modulated by the expression on the NK surface of particular receptors (CD94, p58) specific for defined MHC molecules (Cw1, Cw3, Bw6, B7) on the target cells. Such a specific interaction would induce an 'NK effector inhibition'. The NK reactivity mechanism might have been further evolutionarily modified and adapted by the involvement of other NK receptors, such as CD11b (specific for the C3b factor of the complement) and CD16 (specific for the IgG Fc piece). Cooperation among HSP, MHC, CD11b, CD16, C3b and Fc allows us to propose original models of the activation and cytolysis mechanisms in the NK cytotoxicity and antibody-dependent cell cytotoxicity phenomena.

I have previously assumed that stem tumour cells are 'para-embryonal cells' (PECs) poor or missing in major histocompatibility complex (MHC) antigens. PECs might induce adjoining differentiated hyperplastic cells to also express tumoral phenotype and properties, thus transforming them into 'differentiated para-embryonal cells' (DPECs), MHC-endowed. In such a way, PECs, MHC-lacking, would be automatically surrounded by DPECs, MHC-endowed: this tumour organization was experimentally found by Cordon-Cardo et al in a variety of cancers. Now, I suggest that such a tumour histology might preferentially induce an anti-DPEC T cell immune response which, sparing PECs, might release increasing amounts of DPEC antigens in the peritumour site. DPEC antigens might increase synthesis of specific antibodies and subsequent immunocomplex formation at the peritumour site. Here, abundant immunocomplexes might react through their Fc pieces with CD16 receptors of antibody-dependent cell cytotoxicity (ADCC)-endowed immune cells (natural killer (NK) cells, macrophages, polymorphonuclear cells). These cells would thus be stimulated to secrete their lytic factors before and without their coming into contact with target tumour cells. On the other hand, abundant immunocomplexes at the peritumour site might massively activate the complement system, thus generating large amounts of C3b. C3b might react with CD11b receptors of NK cells, stimulating them to also secrete their lytic factors in an ectopic way at the peritumour site, thus impairing NK cytotoxicity. In such a way, in the absence of ADCC and NK cytotoxicity, a tumour cell enhancement might easily occur. In the light of these ideas, a strategy for antitumour immunotherapy and vaccine is then proposed.

Stem tumour cells would be paraembryonal cells, major histocompatibility complex lacking and able of inducing adjoining cells to become tumour differentiated cells with major histocompatibility complex; thus, they would generate a histological tumour organization into paraembryonal cell clusters surrounded by tumour-differentiated cells. Such an organization, actually found in recent studies, might be one factor responsible for the limits of the immunotherapies carried out so far. But, there might be another, perhaps more important, factor. Analysis of ontogenetic aspects of MHC-nonrestricted immunity would lead, indeed, to the prediction that natural killer clones reactive for stem tumour cells (paraembryonal cells) would be missing in the adult organism, since they would be deleted in particular ontogenetic phases. This might explain why natural killer cells locate only in certain organs and nearly not at all in tumour sites. By such an analysis, possible evolutive and functional correlations between natural killer cells and heat shock proteins, hemopoietic histocompatibility, major histocompatibility complex molecules are suggested. From here, explanations and implications for grafts, pregnancy and tumour immunoprophylaxis arise.

The previously hypothesized paraembryonal nature of tumor cells (1) leads one to suggest, immunologically, the presence in a tumor of two main cell populations: one consisting of either genotypically or phenotypically paraembryonal cells (PECs), with no differentiation MHC (major histocompatibility complex) antigens, and representing the stem tumor cells; the other consisting of phenotypically differentiated-paraembryonal cells (DPECs), with either embryonal or differentiated antigens, rising from neighbour genotypically normal cells induced by PECs. PECs, without MHC antigens, might escape alpha beta TCR (T-cell alpha beta receptor) lymphocyte immunosurveillance, since alpha beta TCR T-cells recognize only MHC-restricted antigens, such as DPEC antigens. On the other hand, PECs might be recognized by gamma delta TCR lymphocytes, known to constitute a more primitive immunosurveillance system, able to recognize non-MHC-restricted antigens. On this ground, several immunological aspects of the tumors are analysed and suggestions for a more effective tumor immunotherapy are given.

Ontogenesis might be considered as the development of phylogenetically consequent genic systems that mainly imply: homoeotic genes and ras protooncogene in segmentation; ras and myc protooncogenes in gastrulation; ras, myc and other nuclear protooncogenes in organogenesis; ras myc, other nuclear and cytomembrane protooncogenes in growth-differentiation. Oncogenesis is considered as the stable regression of a transformed cell into a "para-embryonal" gene-phenotypical condition, and it is usually presented as a three-phased process: mutational events on nuclear protooncogenes-myc in particular-would determine "initiation"; other mutations on cytomembrane protooncogenes-ras, especially-would determine "promotion"; other events would finally prevent the cell from carrying out its genic programme completely, thus maintaining the reiterated expression of primitive genic systems (gastrulation and organogenesis), the embryonal products of which-malignant in an adult organism-would determine tumoral "progression".