Differentiation antigens of hemoblastoses and epithelial tumors: relations to the mechanisms of transformation and progression

The role of mechanisms underlying differentiation is considered in malignant transformation of hemoblastoses and epithelial tumors. In hemoblastoses, differentiation is intimately related to malignant transformation and they are underlain by the same mechanisms. Immunophenotyping of hemoblastoses is fully based on successive stages of their differentiation with characteristic expression of differentiation antigens. Unlike hemoblastoses, epithelial tumors gradually, in the course of progression, lose their differentiation due to the degradation of the connections with the microenvironment, which controls the direction and level of epithelial differentiation. Therefore, carcinomas are characterized by varying degrees of "antigenic simplification", including the epithelial-mesenchymal transition.     

Differentiation mechanisms and malignancy

This review considers the relationship between differentiation mechanisms and the genesis and maintenance of tumor phenotype. To a certain extent, carcinomas preserve differentiation markers of normal tissue, and hemoblastoses precisely reflect the direction and differentiation level of their precursor cells. Both tumor types retain the ability to differentiate. Mechanisms of T and B cell differentiation are reviewed considering the activation of protooncogenes by translocation to the region of tissue-specific genes including the immunoglobulin (Ig) and T cell receptor (TCR) genes. Apart from the classical oncogenes (MYC, PRAD, BCL-2), heterologous differentiation of trans-factors can be activated in a similar manner. Their activation at inappropriate time and place induces oncogenic transformation in a number of hemoblastoses. Chimeric genes and fused proteins are analyzed, including their genesis by specific translocation resulting in transformation and their role in differentiation and maintenance of the tumor phenotype. Induction of terminal differentiation in leukemia can have significant therapeutic effect. These hemoblastoses include hairy cell leukemia, promyelocytic leukemia, and in part chronic myeloid leukemia. Specific attention is given to the role of intercellular interactions in the control of tumor growth and maintenance of a differentiated state of the cells. It is suggested that alterations in these interactions during tumor progression simultaneously stimulate malignant growth and decrease differentiation level, thus inducing re-expression of embryonic antigens in the tumors.     

Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells

Tumor-stroma interactions play a significant role in tumor development and progression. Alterations in the stromal microenvironment, including enhanced vasculature (angiogenesis), modified extracellular matrix composition, inflammatory cells, and dys-balanced protease activity, are essential regulatory factors of tumor growth and invasion. Differential modulation of stromal characteristics is induced by epithelial skin tumor cells depending on their transformation stage when grown as surface transplants in vivo. Tumor cells can regulate the development of a "tumor-stroma" via the aberrant expression of growth factors or induction of growth factor receptors in the stromal compartment. In this context, secretion of the hematopoietic growth factors G-CSF and GM-CSF, constituitively expressed in enhanced malignant tumors, may be good candidates for induction of a tumor stroma through their effect on inflammatory cells. Upon its induction, the tumor stroma will reciprocally influence the differentiation status of tumor cells resulting in a normalization of benign tumor epithelia and the maintenance of a malignant phenotype, respectively. In the HaCaT model for squamous cell carcinoma of the skin, stromal activation and angiogenesis are transient in pre-malignant transplants, however they remain persistent in malignant transplants where progressive angiogenesis is closely correlated with tumor invasion. While continued expression of VEGF and PDGF are associated with benign tumor phenotypes, activation of VEGFR-2 is a hallmark of malignant tumors and accompanies ongoing angiogenesis and tumor invasion. As a consequence the inhibition of ongoing angiogenesis by blocking VEGFR-2 signalling resulted in dramatically impaired malignant tumor expansion and invasion. Comparably, tumor vascularization and invasion was blocked by disturbing the balance of matrix protease activity caused by a lack of PAI-1 in the stromal cells of the knockout mouse hosts. A similar inhibition of tumor vascularization was caused by TSP-1 over-expression in skin carcinoma cells, which also blocked tumor invasion and expansion. On the other hand, when granulation tissue and angiogenesis were only transiently activated as a result of stable transfection of PDGF into non-tumorigenic HaCaT cells, the target cells formed benign, but not malignant, tumors. Collectively, these data show that tumor vascularization, providing intimate association of blood vessels with tumor cells, is a prerequisite for tumor invasion. A potential mechanism for this interrelationship may be the differential regulation of MMP-expression in tumors of different grades of malignancy. In vitro MMP expression did not discriminate between benign and malignant tumor cells unless they were co-cultured with stromal fibroblasts. However, in vivo regulation of MMP expression was clearly dependent on tumor phenotype. While MMP-1 and MMP-13 were down-regulated in benign transplants, they were persistently up-regulated in malignant ones. A tight balance between proteases and their inhibitors is crucial for both the formation and infiltration of blood vessels and for tumor cell invasion, thus again emphasizing the importance of the stromal compartment for the development and progression of carcinomas.     

Terminally differentiating epithelial tissues in primary explant culture: A model of growth and development

Summary Many epithelial tissues are characterized by the presence of basal cells which serve the dual roles of self-renewal and of progression through terminal differentiation, to a functional state. Such tissues, when grownin vitro as primary explants, exhibit a characteristic pattern of outgrowth and development which includes both renewal and efforts toward normal differentiation. The degree of differentiation achieved depends upon conditions of culture and may be modulated in a variety of ways. The human prostate constitutes such a system and offers numerous possibilities for investigating basic control mechanisms in growth and development. Information on a variety of epithelial tissues is reviewed and experimental results using human prostate tissue are presented. The work was supported by grant R26 CA 2365, National Cancer Institute.     

Differentiation Antigens: Dependence on Carcinogenesis Mechanisms and Tumor Progression (A Hypothesis)

The data considered in the paper indicate that a tumor clone resulting from cell transformation, in order to develop into an overt neoplasm, should overcome a microenvironmental constraint. This destroys intercellular contacts and cell interactions with extracellular matrix required for induction and maintenance of epithelium differentiation. The possible reasons for this lie in mutations of genes that control cell adhesion molecules and integrins, as well as proteases secreted by a tumor. These events lead to partial loss of differentiation antigens by a cell or to their incorrect localization in a cell. Simultaneously, the expression of embryo-specific genes is unblocked, leading to overexpression of embryonic antigens and their abnormal secretion into blood, which results in appearance of oncofetal serum markers. Discussed from this point of view are alpha-fetoprotein, the carcinoembryonic antigen, and the prostate-specific antigen, which are used as tumor markers.     

Biology of human papillomavirus (HPV) infections and their role in squamous cell carcinogenesis

Current data implicating the role of human papillomavirus (HPV) infections in squamous cell carcinogenesis may be summarised as follows: animal models have shown that PVs can induce malignant transformation; HPV involvement in both benign and malignant human squamous cell tumours has been demonstrated by morphological, immunohistochemical and DNA hybridisation techniques; HPV infections in the genital tract are venereally transmitted and are associated with the same risk factors as cervical carcinoma; the natural history of cervical HPV lesions is similar to that of CIN, namely, they have the potential to develop into carcinoma in situ; malignant transformation of PV-induced lesions seems to depend on virus type and the physical state of its DNA, e.g., whether or not it is integrated in the host cell DNA; malignant transformation most probably requires synergistic actions between the PVs and chemical or physical carcinogens, or other infectious agents; genetic disposition (at least in animals) significantly contributes to malignant transformation; immunological defence mechanisms of the host are probably capable of modifying the course of PV infections (efficacy in man remains to be elucidated). Many details of the molecular mechanisms, however, still remain to be clarified. Although BPV1 is capable of transforming fibroblasts, the way that papillomaviruses transform epithelial cells is unclear. Which gene is capable of inducing the limited cell proliferation in benign lesions? No model systems exist to provide the answer nor to elucidate the progression to malignant cells and then to invasive cancer. Improved tissue culture systems for in vitro differentiation of keratinocytes should help in elucidating the biology of papillomaviruses and their interaction with cell division and differentiation.