Properties Of Malignant Cells Research Articles

Molecular aspects of the plasma membrane in tumor cells.

It is well known that malignant neoplastic cells are different in their surface properties from their normal counterparts. 1,ZO) Unusual cell-to-cell interactions in the malignant cells are the most important behavior for distinguishing them from their normal counterparts and also for determining the prognosis of patients suffering from cancer. Decrease in or loss of the cell's ability of (1) sorting out each other, (2) mutual adhesiveness, (3) intercellular communication by exchange of small molecules, (4) contact inhibition of both growth and movement affecting the cell density of in vitro culture, and changes in the surface antigenisity, including changes in surface arrangement of various receptors, have been considered hitherto as specific abnormalities in the surface properties of malignant cells. A change in the association of plasma membrane with cytoskeletal structures also seems to have a close relation with these abnormalities. Almost all the details of the molecular mechanisms of these abnormalities, however, remain obscure. In this paper, to clarify some of these molecular mechanisms, we will elucidate some of the molecular events and discuss them in connection with abnormalities of the surface properties in tumor cells based on our analytical results obtained from the plasma memberane of tumor cells.

Organization of type III collagen in benign and malignant ovarian tumors. An immunohistochemical study

Abnormal interaction with the extracellular matrix is a basic property of malignant cells. Type III collagen is a major constituent of the extracellular matrix of soft tissues. Deposition of the aminoterminal propeptide of type III procollagen (PIIINP) was studied in benign (n = 41), borderline (n = 4), and malignant (n = 32) human ovarian tumors using the avidin-biotin-immunoperoxidase technique and affinity-purified antibodies to human PIIINP: It was then compared with the serum PIIINP concentrations of the patients at the time of operation. In malignant tumors, the distribution of PIIINP was irregular both close to the epithelial cancer cells and further away, in the stroma. Another feature typical of malignant tumors was the varying staining intensity of the PIIINP-positive fibers. The benign tumors were characterized by a regular organization and an intensive staining of PIIINP: Borderline tumors showed a slightly decreased staining intensity and altered PIIINP distribution. A significant positive correlation was found between the PIIINP concentration in serum and the degree of irregularity in the distribution of PIIINP: These preliminary results indicate that malignant transformation in ovarian tumors is associated with disintegration of adjacent collagenous structures and with alterations in type III procollagen metabolism, which also leads to increased serum PIIINP levels. They suggest that biochemical or immunohistochemical detection of the PIIINP antigen could be clinically useful in ovarian tumors.

Molecular mechanisms of cancer metastasis

The natural progression of benign tumors to malignancy and metastasis is characterized by their ability to circumvent microenvironmental controls on cellular proliferation, diversity, and positioning, and evolve into heterogeneous phenotypes, a process that probably involves qualitative and quantitative changes in gene expression. The oncogenes and suppressor genes that can effect tumor progression may control important points in the regulation of sets of genes that are ultimately responsible for the cellular alterations seen in highly metastatic cells. Because many cancers metastasize nonrandomly to particular distant sites, their colonization properties cannot be explained by mechanical considerations, such as arrest of tumor cells in the first microcirculatory network encountered. Metastatic cells that show a high propensity to metastasize to certain organs adhere at higher rates to microvessel endothelial cells isolated from their target sites, invade into target tissue at higher rates, and respond better to paracrine growth factors from the target site. These properties depend on multiple tumor cell, host cell, and stromal molecules that are differentially expressed by particular tumor and organ cells and by the organ extracellular matrix. Together these tumor and host factors appear to determine the organ metastatic properties of malignant cells.

Normal nonmetastatic human trophoblast cells share in vitro invasive properties of malignant cells.

First-trimester normal human trophoblast cells show some phenotypic similarities to malignant cells, e.g., rapid proliferation and ability to invade neighboring tissue, including basement membrane in situ, but do not have the ability for unlimited growth or metastasis. The present study examined whether the invasive ability of normal trophoblast cells is an intrinsic property of these cells, independent of the microenvironment provided by the pregnant uterus, and if so, whether they share some of the molecular mechanisms of invasion exercized by metastatic malignant cells. The ability of in vitro grown human trophoblast lines to invade an epithelium-free human amniotic membrane was measured from the temporal kinetics of retention of radioactivity within this membrane resulting from a penetration by 125I-iododeoxyuridine-labeled trophoblast cells. The magnitude of this invasion was compared to that of the highly metastatic human JAR-choriocarcinoma cell line and murine B16F10 melanoma line. Trophoblasts were found to share some of the same molecular mechanisms of invasion with the metastatic cell lines. Inhibitors of collagenase, plasmin, plasminogen, and plasminogen activators completely prevented invasion of the amnion by the trophoblast lines as well as by the metastatic JAR and B16F10 lines. Mersalyl, a compound known to activate collagenase, stimulated invasion by all cell lines tested, including under conditions in which plasmin activity was inhibited. In addition, trophoblasts produced significant levels of type IV collagenase and laminin, both of which appear to be important products of metastatic tumor cells required for basement membrane invasion. It may be concluded from these findings that the invasive property of first trimester human trophoblasts is genetically determined; that the magnitude of amnion invasion cannot differentiate between metastatic cell lines and invasive but nonmetastatic cell lines; and that invasiveness is not a sufficient prerequisite for metastatic ability.

Organ specificity of metastatic tumor colonization is related to organ-selective growth properties of malignant cells.

In cancers such as malignant melanoma, tumor spread or metastasis occurs preferentially to certain organ sites. Mouse B16 melanoma cell sublines that have been selected sequentially in vivo for enhanced blood-borne colonization of lung, brain, or ovary were tested for their survival and growth stimulation in vitro by soluble factors released from suspensions of mouse lung, brain, liver, ovary or kidney tissues. In general, the growth rate of lung-colonizing B16 cells was stimulated by high concentrations of lung-tissue-derived factors significantly more than by factors from the other tissues, whereas the growth rate of ovary-colonizing B16 cells was stimulated by ovary or lung-tissue-derived factors significantly more than by factors from the other tissues. In contrast, the growth of brain-colonizing B16 cells was not stimulated by factors released from brain tissue. When it occurred, stimulation of B16 cell growth by factors released from mouse organ tissues was dose-dependent. Liver tissue factors, and at high concentrations kidney tissue factors, inhibited cell growth of the B16 sublines, an inhibition correlating with the low potential of B16 cells to colonize liver and kidney in vivo. In addition to preferential target-organ cell adhesion found previously with B16 sublines (Nicolson et al., 1985a), the present results suggest that metastasis to specific organ sites is also dependent on the survival and growth of B16 cells affected by soluble organ-derived factors.

A mos oncogene-containing retrovirus, myeloproliferative sarcoma virus, transforms rat thyroid epithelial cells and irreversibly blocks their differentiation pattern.

Differentiated, cloned rat thyroid epithelial cells (424 cells) were infected with a wild-type and a temperature-sensitive strain of the myeloproliferative variant of the Moloney murine sarcoma virus. The thyroid cells were productively infected and transformed by both virus strains and displayed some of the typical properties of malignant cells, such as morphological changes, growth in soft agar, and in vivo tumorigenicity. The acquisition of the transformed phenotype by the virus-infected cells was accompanied by a loss of the typical differentiated features of the thyroid epithelium, such as thyroglobulin (TG) secretion, iodide uptake, and dependence for growth on six factors including thyrotropin, the physiological thyroid stimulator. TG mRNA could not be demonstrated in cells transformed by both viral strains, suggesting a block at the level of the TG gene transcription. While the transformed state of the cell clones infected with the temperature-sensitive strain could be reverted by shifting the cultures to the temperature nonpermissive for transformation (39 degrees C), no reversion of the differentiated functions took place after such a shift, showing that the v-mos oncogene irreversibly shuts off the differentiation of thyroid epithelial cells in vitro. These results demonstrate, for the first time, an oncogenic potential of the v-mos oncogene family towards differentiated epithelial cells in vitro.

DNA and S-phase representation in human growth hormone producing pituitary adenomas.

The DNA contents of 33 pituitary adenomas from patients with acromegaly were analysed with flow-cytofluorometry. Degrees of ploidy and the proliferation rate, expressed as percentage of cells in S-phase, were determined. The aim was to compare these morphological and functional tumour properties with clinical and laboratory parameters to establish a possible relation and to further elucidate the characteristics of these tumours. In 15 tumours (45%) diploid DNA pattern were found, while 18 (55%) showed varying degrees of aneuploidy. The frequency of cells in S-phase showed wide variations and were equally distributed in diploid and aneuploid tumours. Duration of symptoms, age at diagnosis, preoperative growth hormone (GH)- and prolactin (Prl)-levels, tumour size and grade of invasive tumour growth as determined by radiological estimations, did not correlate to ploidy or grade of proliferation. The lack of correlation between DNA pattern and proliferation rate in relation to clinical, laboratory and radiological parameters in tumours causing acromegaly contrasts to the documented relation between the degree of ploidy, cells in proliferation and grade of malignancy reported in tumours of other sites. The 55% aneuploid GH producing tumours indicate a certain malignant transformation. The high frequency of cells in S-phase in several GH secreting tumours completes the malignant morphological and functional cell properties. The benign character of tumours causing acromegaly is therefore in contrast to these findings. The lack of clinical significance of the DNA pattern and the frequency of cells in proliferation in GH producing tumours and the benign character despite malignant cell properties in most of these tumours are difficult to explain.(ABSTRACT TRUNCATED AT 250 WORDS)

Photobiologic considerations in photoradiation therapy.

Hematoporphyrin derivative (HPD) photoradiation therapy of tumors depends on selective cell injury. The major selectivity of the treatment rests on an increased amount or prolonged retention of certain constituents or biotransformation products of HPD in tumor tissues. This increased concentration or prolonged retention results from some incompletely understood biochemical properties of malignant cells (protein binding, membrane changes, aberrant biotransformation) or cancer tissue (increased blood supply, avascular zones, absent lymphatics). Identification of the most active components of HPD and a better understanding of the mechanisms of prolonged retention may permit improved treatment design to achieve more selective destruction of tumor tissue.KeywordsStratum CorneumRegular ReflectanceProlonged RetentionNear Infrared RadiationHematoporphyrin DerivativeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Concomitant Tumor Immunity and the Resistance to a Second Tumor Challenge

Publisher Summary Concomitant tumor immunity is considered as a synonym for the immunity of tumor-bearing mice in contrast to the immunity of immunized mice. Indeed, growth of immunogenic tumors is accompanied by the development of a specific immune response and by the production of immune lymphocytes or humoral antibodies that can be determined by different in vivo or in vitro techniques. Antitumor immune response was assessed by the level of resistance of tumor-bearing or immunized mice to a second challenge with tumor cells. From the immunologic point of view, the presence of the antigenic material in increasing amounts is not required to maintain the immune reactions. Surgical removal of the growing tumor after the development of antitumor response leaves these mice immune to the second tumor challenge, and immune cytotoxic cells in these mice can be detected. Numerous experimental data demonstrated that the surgical excision of the primary tumor removes the inhibitory influence and accompanies the acceleration of metastatic growth. Similar mechanisms might be responsible for the inhibition of the growth of spontaneous metastases or tumor cells reinoculated into tumor-bearing host. Depending on immunobiological properties of malignant cells, the contribution of immunologic and nonimmunologic mechanisms in this inhibition could be different. Further investigations of the mechanisms of these phenomena can contribute to understanding the mechanism of malignant disease and developing effective methods for treatment of cancer patients.

The role of glycoconjugates in metastatic melanoma blood-borne arrest and cell surface properties.

The role of glycoconjugates in cell surface and blood-borne implantation properties of murine metastatic melanoma sublines of low (B16-F1) or high (B16-F10) potential to colonize lungs was investigated by treating melanoma cells with the antibiotic tunicamycin. This drug prevents glycosylation of glycoproteins by inhibiting the formation of lipid-linked oligosaccharide precursors. The degree of tunicamycin-mediated modifications in glycoproteins was assessed by monitoring the decrease in cell surface sialogalactoproteins by binding of 125I-labeled Ricinus communis agglutinin I. Scanning electron microscopy of tunicamycin-treated B16-F1 and B16-F10 cells showed morphologic changes such as cell rounding and formation of numerous surface blebs. Tunicamycin-treated B16-F1 and B16-F10 cells lost their lung colonization abilities when injected intravenously into C57BL/6 mice, concomitant with lowered rates of adhesion to endothelial cell monolayers, endothelial extracellular matrix (basal lamina), and polyvinyl-immobilized fibronectin in vitro, suggesting that this drug inhibits experimental metastasis by modifying the surface glycoproteins involved in determining the adhesive properties of malignant cells.

Characterization of a human ovarian teratocarcinoma‐derived cell line

A cell line (PA I), derived from human ovarian teratocarcinoma cells, was obtained by culturing ascitic fluid cells from a patient with recurrence of malignant ovarian teratoma. During early passages the cultured cells showed a variable morphology, a long doubling time, and a low plating efficiency (2%). After about 50 passages in vitro, a cell population which was more homogeneous and resembled embryonal carcinoma cells were obtained. These cells had a shorter doubling time (26 h), and increased plating efficiency (77%). The early-passage cells were aneuploid (P 24) whereas the late-passage cells had a normal diploid karyotype with one balanced translocation between chromosomes No. 15 and No. 20 (P 224). Details of the karyotype suggest that the cells are heterozygous, i.e. derived from a stage before the first meiotic division. One of the two X chromosomes were inactive, and the cells expressed HLA antigens (A28 and B12), and beta 2-microglobulin. Expression of F9 antigen, characteristic of two-cell and later preimplantation embryos, was absent, while expression of PCC4 antigen, expressed also by blastocysts, was present. This finding suggests that the line might express some embryonic characteristics. The PA I cell line maintained in monolayer cultures showed several characteristics of malignant cells. The proportion of malignant cells increased with successive passages in vitro. The late-passage cells represented a fairly homogenous population of malignant cells similar to embryonal carcinoma cells. Late-passage PA I cells, when seeded under conditions that prevented attachment of cells to the substratum, formed embryoid bodies consisting of an inner core of cells similar to embryonal carcinoma cells, surrounded by a rind of endoderm-like cells. These two cell layers were separated by a basement membrane-like structure containing fibronectin. The core embryonal carcinoma cells expressed high alkaline phosphatase activity whereas the endoderm-like cells had low alkaline phosphatase activity. Embryoid bodies seeded on an adhesive substratum formed polycystic structures divided by layers of epithelial-like cells and containing extracellular fibrils similar to collagen type I or III. In these cultures, further limited differentiation into endoderm-like, epithelial-like cells and pigmented cells was observed. Morphological differenciation of undifferentiated PA I cells into endoderm-like cells in monolayer cultures could be obtained by treatment with BrdUrd or by plating in low serum concentration and at low density. Cells with characteristic fibrillar distribution of fibronectin and actin microfilament bundles were then observed, indicating formation of cells lacking properties of malignant cells. As indicated by these results, the PA I cell line, in spite of a limited capacity to differentiate in vitro, shares some of the properties of mouse teratocarcinoma cell lines and might therefore serve as a useful model for studies on some developmental mechanisms in human cells.

The relationship between tumorigenicity, growth in agar and fibrinolytic activity in a line of human osteosarcoma cells.

The TE-85 osteosarcoma cell line has several of the in vitro properties of malignant cells, including colony formation in agar, but has low extracellular fibrinolytic activity and no capacity to form tumors in ATS-treated hamsters. Some TE-85 cells clones (clones 2, 4 and 6) have increased fibrinolytic activity but do not form tumors in hamsters. TE-85 cells infected with mammalian transformation-defective viruses have low (FeLV) or increased (RD-114 virus) levels of fibrinolytic activity and do not form tumors in hamsters. TE-85 cell either nonproductively infected with Ki-MSV or productively infected with M-MSV (RD-114), have fibrinolytic activity and can form tumors in hamsters. The MSV gene(s) but not colony formation in agar or extracellular fibrinolytic activity appears to be capable of rendering TE-85 cells tumorigenic in ATS-treated hamsters.

Chromosome analysis and agglutination by concanavalin A of primary simian‐virus‐40‐induced tumors

Tumors induced by SV40 virus in newborn and adult Syrian hamsters were analyzed for their growth properties in vitro, transplantation, agglutination with concanavalin A and chromosome constitution. Following transfer to culture flasks tumor cells grew for 2-3 weeks, then went through a "degenerative phase". Eventually lines were established which became adapted to in vitro culture conditions. Agglutination properties of these tumor cells were similar to those of cells transformed in vitro with SV40 virus. Of five subcutaneous and six intratesticular tumors that were analyzed for their chromosome constitution, all had a hypotetraploid chromosome number distribution. The results of the chromosome studies suggest a similiar pattern in the evolution of malignant properties of cells transformed in vitro and in vivo following infection with SV40 virus.

Antiinflammatory effects of murine malignant cells.

Development of teratocarcinoma does not impair immunization of mice against Listeria monocytogenes. Endotoxin injection a short time before tumor cell inoculation allows the growth of teratocarcinoma in non syngenic mice despite immune stimulation. In contrast with this absence of impaired systematic immunity, teratocarcinoma cells were found to repulse macrophages in vitro. This effect on macrophages was also found with three other malignant cells and with trophoblast cells. In vivo, teratocarcinoma cells were found to impair local inflammation. These cells and other malignant cells are able to produce a compound(s) of molecular weight between 10(3) and 10(4), which prevents inflammatory reaction. These results suggest that mouse teratocarcinomas and other tumors by-pass the host immunological system of surveillance by at least two mechanisms: a direct toxic effect on macrophages and the release of an inhibitor of inflammation. The possible relations between these properties of malignant cells and physiological functions of trophoblast are discussed.

Epstein-barr virus-negative human malignant T-cell lines.

Two lymphoblastoid lines, CCRF-CEM and HSB-2, with properties of malignant cells, derived from children with leukemia secondary to lymphosarcoma, have T-cell properties and lack Epstein-Barr virus antigens.

In vitro culture of cells isolated from dimethylnitrosamine-induced renal mesenchymal tumors of the rat.

Cells isolated from dimethylnitrosamine (DMN)-induced renal mesenchymal tumors and established in long-term culture retained various properties of malignant cells. In contrast to cells cultured from normal rat kidney cortex, tumor cells appeared to have an unlimited growth potential, were able to establish clones at low seeding rates and to produce colonies in carboxymethyl cellulose (CMC) gel and on chick embryo chorioallantoic membrane (CAM), and were agglutinable by concanavalin A. Cells of tumor lines were quantitatively smaller than normal cells, had a higher nucleus: cytoplasm ratio, a broader range of multiple nucleoli and a higher mitotic index.

A model of cancer studied by a computer

A digital computer has been used to study the reaction of the liver model described earlier ( Sendov & Tsanev, 1968) in the case when the functional operon D M is irreversibly blocked. We show that in such a case a cellular system is obtained which exhibits the growth properties of malignant cells: possible latency, growth stimulatory effect of different agents, diversity of the proliferative reaction. These results are consistent with the hypothesis that the induction of cancer cells is related to the irreversible blocking of a special functional operon interconnected with the mitotic operons in a regulatory genetic circuit.

The effect of the chlorethylamine preparations lonin-4 and lonin-3 on the antigenic and virulent properties of malignant cells

A study was made of the antigenic and virulent properties of the Ehrlich adenocarcinoma cells subjected to the action of the preparations lonin-4 and lonin-3. Investigations were carried out on guinea pigs by means of anaphylaxis with reaction desensitization, as well as on mice subcutaneously vaccinated with adenocarcinoma cells, treated in vivo and in vitro with lonin-4 and lonin-3. The results of investigations clarified to a degree the action mechanism of the studied chlorethylamino preparations and some problems concerning the immunobiological cancer cell variability.

CANCER BIOLOGY: VIRAL AND EPIGENETIC*

CANCER BIOLOGY: VIRAL AND EPIGENETIC*