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Local infiltration of T-lymphocyte subsets as a prognostic indicator in patients with nasopharyngeal carcinoma.

We studied tumor-host interactions in 47 patients with NPC. The local infiltration of T-lymphocyte subsets was investigated by an immunoperoxidase technique using monoclonal antibodies. Biopsy specimens of patients without cervical metastasis showed more T-lymphocyte (T11) infiltration. The amount of Leu-3a (helper/inducer) and T8 (cytotoxic/suppressor) cell infiltration did not correlate with the age, sex, clinical stage, and peripheral blood T4 and T8 cells of the patients. A higher incidence of Leu-3a cell infiltration was found in patients with high serum IgA antibody titers to EBV VCA. A trend of better prognosis was revealed in those cases with no or slight stromal T8 cell infiltration. A local immune response was found to exist which may prevent the spread of NPC to the cervical nodes, but this needs further study to evaluate the local infiltration of T-lymphocyte subsets as a prognostic indicator.

Adult↗

Inability of inline pressure monitoring to predict or detect infiltration of peripheral intravenous catheters in infants.

Monitoring of inline intravenous pressure as a method for predicting or detecting infiltration of peripheral catheter sites in infants was evaluated. Inline intravenous pressure was measured every 30 minutes in infants less than 12 months of age who had standardized peripheral catheters through which they were receiving a continuous infusion. Pressure was measured by an inline pressure transducer, and the signal was recorded by a strip chart recorder. Physical activities or manipulations of the patients were recorded simultaneously with each pressure reading. The catheter site was inspected hourly for clinical signs of infiltration. There was no significant difference in baseline or final pressure measurements between patients whose catheter sites became infiltrated (n = 20) and patients whose catheter sites did not (n = 22). Likewise, changes in pressure from baseline did not differ between the infiltrated and noninfiltrated groups. At 12 hours before the final reading, pressures for the infiltrated group did not differ significantly from pressures for the noninfiltrated group, nor did these values differ from the respective baseline values. Over the final 12 hours of catheterization, mean slopes (changes in pressure over time) for the two groups did not differ significantly from 0 or from each other. Intrapatient specificity and sensitivity of the method and the false-alarm rate were clinically unacceptable. Monitoring of inline intravenous pressure is not useful for predicting or detecting infiltration of peripheral catheter sites in infants.

Catheterization, Peripheral↗

Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating systemic atrophy affecting the upper and lower motor neurons. The etiology is unknown, but one theory of pathogenesis supposes that the motor system is affected by abnormal immune responses. We have studied the prevalence and extent of lymphocytic infiltration, previously reported as a rare finding in the ALS spinal cord. Application of monoclonal antibodies against macrophages, T- and B-cells to spinal cords from 48 ALS patients disclosed a cellular mononuclear infiltrate in 38 specimens (79%), intense enough to be revealed by routine neuropathological techniques in 6 of them (12.5%); the remaining 10 cords (21%) exhibited no infiltrates. Since duration and clinical signs of the preceeding illness were the same in cases with and without infiltrates, we consider it unlikely that such infiltrates are entirely secondary to atrophy of the cord. As Wallerian degeneration is not accompanied by infiltrates of lymphocytes, their presence in the cord tracts of our material throws doubt on the conventional view that tract degeneration in ALS is exclusively Wallerian.

Adult↗

Expression of lymphocyte activation markers in benign cutaneous T cell infiltrates. Discoid lupus erythematosus versus lichen ruber planus.

The expression of lymphocyte activation markers (IL2 receptors, transferrin receptors and HLA-DR) was examined in cutaneous lymphoid infiltrates of 12 patients with lichen ruber planus (LP) and 10 individuals with discoid lupus erythematosus (DLE). The cell infiltrates in both conditions were generally of considerable size. The vast majority of the infiltrating cells were T cells. The reactivity of the anti-IL2 receptor antibody used was confined to lymphocytes. In patients with LP 26 +/- 17% of the infiltrating cells were IL2 receptor positive, 20 +/- 8% carried transferrin receptors and greater than 90% HLA-DR. In patients with DLE less than 1% were IL2 receptor positive, less than 5% carried transferrin receptors and greater than 90% were HLA-DR positive. These data indicate that IL2 receptor expression distinguishes the infiltrating T-lymphocytes in LP and DLE, although in both conditions the vast majority of the infiltrating cells were activated as revealed by their expression of HLA-DR.

Adult↗

Scanning microscopy of resin infiltration patterns in acid-etched incisor enamel.

Previous studies have described the surface morphologic characteristics of acid-etched enamel. The purpose of this investigation was to examine the patterns of resin infiltration into the etched enamel. Fourteen, human, incisor teeth, extracted because of advanced periodontal disease, were etched on the labial surfaces for 60 seconds with 37% phosphoric acid, washed in tap water, and then air-dried. A self-cured enamel resin was applied to the etched labial surface and supported with epoxy. The teeth were dissolved in formic acid. The resin remnants were cleaned in water, dried, mounted on specimen stubs, coated with sputtered gold, and examined in a Scanning electron microscope (SEM). Resin infiltration patterns were photographed in the SEM at a magnification of 400 in 0.125-mm2 areas of the incisal, middle, and gingival thirds of each labial surface. Resin infiltration patterns were scored according to the correspondence with the rod-core, rod-periphery, and irregular acid-etch patterns seen in enamel. The distribution of resin infiltration patterns was as follows: rod-core, 9.7%; rod-periphery, 40.5%; and irregular, 49.7%. The values were averaged over all the surface areas. Infiltration patterns into the etched enamel exhibited deep interperikymata resin penetration. Subsurface channeling of resin was responsible for the pattern seen in irregular etch and was the most common form of infiltration in the gingival region. Subsurface channeling may be related to the development of micropores observed in incipient carious lesions. Deep monomer penetration and channeling may be important factors in mechanical attachment.

Acid Etching, Dental↗

[Infiltration of bile duct carcinoma along the wall].

The characteristics of the infiltration of bile duct carcinoma along the wall were studied from 25 cases with resection. The histologic mode of the spread of carcinoma was the mucosal infiltration in 1 case, mucosal and transmural infiltration in 2 cases, transmural infiltration in 22 cases. The average distance from the gross margin of the tumor to the margin of spread of growth in the bile duct as determined microscopically was 19.1 mm in the direction of the liver (the longest was 85 mm), and 5.8 mm toward the duodenum (the longest was 20 mm). The distance of the polypoid or nodular type of the gross appearance of the tumor is shorter than that of the infiltrating type. The polypoid type showed inverted U-type in obstructive or stenotic feature of bile duct radiologically and the infiltrating type showed U-type, V-type or constricted type. The distance of the tubular adenocarcinoma in histological cellular type tended to be longer than that of papillary or undifferentiated type. The severer the invasion of the carcinoma to the lymphatic vessels was, the longer the distance was.

Adenocarcinoma, Papillary↗

Demonstration of intratumoral infiltration of tumor-specific Lyt-1+2- T cells mediating delayed-type hypersensitivity response and in vivo protective immunity.

The present study demonstrates the intratumoral infiltration of lymphocytes mediating anti-tumor delayed-type-hypersensitivity (DTH) responses as well as in vivo protective immunity. The surface phenotype and tumor specificity of these effector lymphocytes were determined. X5563 tumor-infiltrating lymphoid cells were obtained from the tumor mass of syngeneic C3H/HeN mice 2 weeks after the intradermal inoculation of 10(6) viable X5563 tumor cells. These lymphoid cells consisted of Thy-1-positive (29-35%), surface immunoglobulin-positive (16-29%), large granule-positive (15-25%) and esterase-staining-positive (10-20%) cells. They were tested for anti-X5563 DTH responses by utilizing a local adoptive transfer system and for tumor-neutralizing activity in a Winn assay. The results indicate that X5563 tumor-infiltrating lymphoid cells exhibited appreciable anti-X5563 DTH responses and conveyed complete protection against the tumor. Treatment of these lymphoid cells with anti-Thy-1.2 or anti-Lyt antibodies plus complement revealed that the in vivo anti-tumor immune responses were mediated predominantly by a Lyt-1+2- T cell subset. Such Lyt-1+2- T cell-mediated immunity was tumor-specific, since X5563-infiltrating and syngeneic MH134 hepatoma-infiltrating cells exhibited DTH response and tumor-neutralizing activity selectively against the respective tumor cell types. Thus, these results indicate that tumor-specific in vivo-protective Lyt-1+2- T cells infiltrate into the tumor mass. The results are discussed in the context of 1) the interrelation of DTH responses and the tumor protection mediated by the Lyt-1+2- T cell subset and 2) possible cellular interactions between Lyt-1+2- T cells and co-existing nonspecific tumoricidal effector cells such as macrophages.

Animals↗

Characterization of lymphocytic infiltrates in normal, preneoplastic, and neoplastic mouse mammary tissues.

Lymphocytic infiltrates were isolated from normal, preneoplastic, and neoplastic mouse mammary tissues. The surface markers on the infiltrating lymphocytes were characterized by immunofluorescent staining and flow cytometry. Preneoplastic and neoplastic tissues contained 10- to 20-fold more in situ lymphocytes than did the normal pregnant gland. Most of these lympocytes were T-cells. Relative to the T-cells in normal gland, the T-cells in C4 preneoplastic hyperplastic alveolar nodules and their spontaneous tumors have shifted in favor of the killer-suppressor subpopulation. This shift of T-cell subpopulations was a localized phenomenon and was not seen in the lymph nodes of hyperplastic alveolar nodules and tumor bearing mice. C4 lesion infiltrating cells also contained a subpopulation of lymphocytes that expressed 5- to 6-fold more LFA-1 antigen (lymphocyte function associated antigen-1) than did normal lymph node cells. The infiltrating lymphocytes of mammary tumors from cloned cell lines, on the contrary, had the same staining profile as did the lymphocytes from normal gland. Since most studies with human breast cancer infiltrates have demonstrated increased killer/suppressor T-cells and the presence of activated lymphocytes (J. Hurlimann and P. Saraga, Int. J. Cancer, 35: 753-762, 1985; H.L. Whitwell, H.P.A. Hughes, M. Moore, and A. Ahmed, Br. J. Cancer, 49: 161-172, 1984; and J.A. Ledbetter, R.V. Rouse, H. Spedding Micklem, and L. Herzenberg, J. Exp. Med., 152: 280-295, 1980) the C4 hyperplastic alveolar nodules and spontaneous tumor system may be a more relevant model for studying breast cancer infiltrates.

Animals↗

Expression of histocompatibility antigens and characterization of mononuclear cell infiltrates in normal and neoplastic colorectal tissues of humans.

Serial frozen sections were prepared from 22 colorectal carcinomas. Additional samples were obtained from the adjacent normal bowel in 10 patients, from 6 concomitant adenomas in 5 patients, and from another 4 isolated adenomas. Mononuclear cell infiltrates were stained by the indirect immunoperoxidase technique with the use of a panel of 6 mouse monoclonal antibodies to human leukocyte antigens. The degree of infiltration was graded from 4 (heavy) to 0 (nil). The colorectal carcinomas and adjacent normal bowel showed an equal degree of leukocyte infiltration (HLe-1), graded 3-4 in 8 cases and 2-3 in the other 2 cases. In 7 carcinomas cytotoxic-suppressor T-lymphocytes (UCHT-4) graded 2-3 predominated over helper T-cells (OKT-4) graded 0-1. By contrast, in the adjacent normal bowel cytotoxic and helper cells were present in equal numbers. Among the adenomas leukocyte infiltration was grade 4 in 9 and grade 3 in 1. In 9 of the 10 adenomas cytotoxic cells graded 2 predominated over helper cells graded 0-1. The number of helper cells was equivalent among 6 concomitant adenomas and carcinomas from 5 patients. Adenomatous epithelial cells expressed class II major histocompatibility complex antigens (OKIa-1). However, carcinomatous or normal epithelium showed only faint staining with OKIa-1. The similarity in cell infiltration is consistent with an adenoma-carcinoma sequence. The predominance of cytotoxic cells in carcinomas that expressed class I major histocompatibility complex supports the association between lymphocyte infiltration and a favorable prognosis.

Adenoma↗

Histological observation of the submandibular gland with special reference to the focal lymphocytic infiltration.

Focal lymphocytic infiltration of the submandibular gland was investigated on the autopsy cases. The materials examined were 340 cases without the collagen diseases and 28 cases with collagen diseases. Of the 28 cases with collagen diseases, 20 were systemic lupus erythematosus, 2 with the coexistence of systemic, lupus erythematosus and Sjögren's syndrome, 4 with rheumatoid arthritis and 2 with progressive systemic sclerosis. Among the cases without the collagen diseases, the focal lymphocytic infiltration was seen in 154 cases (74%) of 209 males and in 94 cases (71%) of 131 females. All 28 cases with collagen diseases had a focal lymphocytic infiltration. The incidence of grade 3 or severe infiltration was 4% in the males and 14% in the females in the cases without the collagen diseases, 65% in the 20 cases with systemic lupus erythematosus, 50% in the 4 cases with rheumatoid arthritis and 50% in the 2 cases with progressive systemic sclerosis. No cases of very severe infiltration were found, which were seen in the classical Sjögren's syndrome, in both cases with and without the collagen diseases. Hyperplastic change in the ductal cells, which can be called an epimyoepithelial island, was found in 23% of the cases with collagen diseases. These observations suggest that the focal lymphocytic infiltrations is a focal sign of the immunologic disorder of the submandibular gland in the collagen disease.

Adolescent↗

Peri-islet infiltrates of young non-obese diabetic mice display restricted TCR beta-chain diversity.

To define the clonal diversity of autoreactive T cells associated with the induction of type 1 diabetes, we characterized TCR expression in the earliest detectable islet infiltrates of non-obese diabetic (NOD) mice. The islets of young NOD females were examined for V beta and J beta germ-line gene usage and V(D)J beta junctional sequence diversity. The results from 7-wk-old mice corroborate prior studies demonstrating that the T cell repertoire of islet infiltrates diversifies early in the inflammatory process. In contrast, examination of 4-wk-old NOD mice showed that TCR-beta expression in the peri-islet infiltrates was restricted both in V beta and J beta gene utilization and, most significantly, in V(D)J junctional sequence diversity. Islet-infiltrating T cells from young mice included V beta 3+ T cells, despite the presence of a mammary tumor virus-3-associated superantigen that deletes the majority of immature V beta 3+ thymocytes in NOD mice. Few other TCR V beta types were repeatedly detectable in early stage infiltrates. V(D)J junctional sequence diversity was evaluated in cDNA libraries made from the islets of young NOD mice. Analysis of these clones revealed limited junctional CDR3 diversity in early-infiltrating T cells, as compared with lymph node T cell libraries. Evaluation of TCR expression in individual islets revealed CDR3 sequence conservation between animals and among islets from a single animal. These results suggest that T cells bearing limited TCR-beta-chain diversity contribute to the inductive phases of autoimmune diabetes.

Amino Acid Sequence↗

Limited TCR repertoire of infiltrating T cells in the kidneys of Sjögren's syndrome patients with interstitial nephritis.

To analyze the mechanism of interstitial nephritis in patients with Sjörgren's syndrome (SS), we examined the TCR repertoire of infiltration T cells in kidney, labial salivary glands, and PBLs using a PCR. The repertoire of the TCR V beta gene on infiltrating T cells from the kidneys of SS patients was more restricted than those on infiltrating T cells in labial salivary glands and PBL. The TCR V beta 2 gene was expressed predominantly in six of seven (86%) SS patients. Junctional sequences of cDNAs encoding the V beta 2 gene on infiltrating T cells in the kidneys of five SS patients showed that some of the cells expanded clonally, indicating Ag-driven stimulation rather than superantigen-induced proliferation. The same V beta 2 clones in the kidney were not detected in labial salivary glands of the same SS patients; the conserved amino acid (arginine at position 96) in the CDR3 region of the V beta 2 gene was found at a frequency of 48.0% in the kidney, whereas it was detected in only 15.4% of the clones in lips. In conclusion, these findings suggest the possibility that T cells that infiltrate the kidneys of SS patients with interstitial nephritis might recognize different autoantigens than those that infiltrate labial salivary glands.

Amino Acid Sequence↗

Gene analysis in 18 cases of cutaneous lymphoid infiltrates of uncertain significance.

BACKGROUND AND DESIGN: Patients with cutaneous lymphoid infiltrates that appear reactive histologically and immunophenotypically may develop clinically overt cutaneous lymphoma, suggesting the possibility of misdiagnosis by classical methods. We investigated DNA rearrangement in such cases of lymphoid infiltrates of uncertain significance to determine whether this more sensitive method could detect an occult monoclonal lymphoid proliferation. METHODS AND PATIENTS: Skin biopsy specimens were taken from 18 cutaneous lymphoid infiltrates diagnosed as reactive on the basis of clinical, histopathological, and immunohistochemical criteria. Specimens included 12 cases with mixed lymphoid infiltrates rich in polytypic B cells and inconstant follicle formation and 6 cases with exclusive T-lymphoid infiltrates. Southern blot analysis for immunoglobulin and T-cell-receptor beta-chain gene rearrangements was performed in all cases. RESULTS: No specimen showed T-cell-receptor beta-chain gene rearrangement. Clonal immunoglobulin gene rearrangement was demonstrated in one case with polytypic B cells, but no clinical malignancy has appeared 19 years after disease onset duration and 7 years after detection of the B-cell clone. CONCLUSIONS: In the present series, the results suggest that histological and immunohistological criteria are appropriate to establish the diagnosis of most cases of cutaneous lymphoid infiltrates. The detection of a B-cell clone is remarkable by absence of clinical malignancy, suggesting that such a discovery does not necessarily mean an aggressive evolution. Nevertheless, there is presently no way to predict the prognosis of a clonal lymphoid proliferation, indicating that a long-term follow-up is necessary.

Adult↗

Eosinophilic infiltration of the liver in primary biliary cirrhosis: a morphological study.

Eosinophils and their secretory proteins are important in necroinflammatory processes. In this study we surveyed eosinophilic infiltration of the liver in 176 liver biopsy specimens from patients with primary biliary cirrhosis. A considerable number of eosinophils were found in the portal tracts in 51 of these specimens (29%), whereas this finding occurred in only 2 of 50 (4%) specimens from patients with viral chronic active hepatitis. Eosinophilic infiltration of the portal tracts was focal. These eosinophils were immunohistochemically shown to contain the secreted form of eosinophilic cationic protein. Grades of eosinophilic infiltration of the portal tracts were higher in those livers with higher grades of lymphoplasmacytic infiltration, granulomas and florid duct lesion in the portal tracts, and they were lower in those livers with higher grades of bile duct disappearance and orcein-positive granuoles in hepatocytes. In the livers of patients with primary biliary cirrhosis, eosinophils were abundant around the damaged bile ducts, around the portal vein branches and at the marginal regions, and they were scattered in the portal tracts, whereas only the last pattern was seen in viral chronic active hepatitis. Peripheral blood eosinophils tended to be increased in primary biliary cirrhosis patients with higher grades of eosinophilic infiltration of the portal tracts. Eosinophilic infiltration of the portal tracts may play a role in immunological injuries of the interlobular bile ducts in primary biliary cirrhosis.

Adult↗

Vascular lesions in biopsy specimens devoid of cellular infiltrates: qualitative and quantitative immunocytochemical studies of human cardiac allografts.

Biopsy specimens from 80 cardiac allografts were studied immunocytochemically with nine antibodies selected to identify cellular, immunologic, and vascular aspects of rejection. Results from these experiments were converted to a numeric base and used to calculate rejection indexes for each of these aspects of rejection. Pretransplantation biopsy specimens of donor hearts were studied to determine normal values, and clinical, catheterization, and conventional biopsy findings were used to classify patients as stable or unstable. The standard deviation of cellular and immunologic reaction indexes were overlapping for stable and unstable patients, but the vascular indexes for these patient groups were significantly different, suggesting that vascular damage defines clinical instability in cardiac allograft recipients. To study the vascular index in the absence of cellular infiltrates, biopsy specimens from 80 allografted hearts were selected to represent 40 patients with cellular infiltrates and 40 patients devoid of infiltrates. The results of this analysis revealed no difference in the vascular index between hearts that contained or did not contain infiltrates; the spectrum of vascular damage between the groups ranged from trivial to severe, suggesting that vascular damage was not dependent on cellular infiltrates. Concluding that these were independent events was not possible, however, because none of the hearts continuously were devoid of cellular infiltrates. Two groups of patients with significantly different vascular indexes then were studied for a systemic manifestation of coagulation by measurement of their thrombin times. The group with low vascular index was found to have significantly prolonged thrombin times compared to the group with high vascular index, and a trend to less prolongation of thrombin times was observed in another group with high cellular index. The relation of these results with cardiac allograft vasculopathy is not established, but the results suggest hitherto unexplored roles for quantitative expressions of hemostasis, fibrinolysis, and anticoagulation in the pathophysiology of vascular disease in allografts.

Adult↗

Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation.

Colon cancer cells express potentially immunogenic proteins but are not rejected by the immune system. To induce an effective immune response, antigenic peptides have to be presented to T lymphocytes by professional antigen-presenting cells in association with HLA class II molecules. Antigen-presenting cells also have to express B7 family molecules, B7-1 and B7-2, which deliver the costimulatory signals that are required to prevent T cell anergy. We studied B7-1 and B7-2 expression by the antigen-presenting cells that infiltrate colorectal cancer stroma. In 25 samples of colorectal carcinomas, a panel of monoclonal antibodies was used to label macrophages, dendritic cells, and T lymphocytes that infiltrate the tumor stroma and the morphologically normal distant mucosa. The expression of HLA class II and B7 molecules involved in T-cell activation was studied using specific monoclonal antibodies. Biopsy pieces from two patients with active Crohn's disease were used as controls. All of the samples were heavily infiltrated by macrophages and/or dendritic cells that strongly expressed HLA class II molecules. In contrast, antibodies to B7-1 and/or B7-2 stained no cells in 16 of the 25 samples of colorectal tumors and less than 1% of the inflammatory cells that infiltrated tumor stroma of the other nine tumor samples. B7 molecules were also poorly expressed by rare cells in the lamina propria of the morphologically normal colorectal mucosa. In contrast, many inflammatory cells that infiltrated the two Crohn's disease samples strongly expressed B7-1 and B7-2, especially in the granulomas. We conclude that most HLA class II+ inflammatory cells that infiltrate colorectal cancers do not express the B7-1 and B7-2 costimulatory molecules. This defect may contribute to the failure of the immune system to recognize tumor cells as antigenic.

Adenocarcinoma↗

[Pseudotumorous cardiac infiltration in a patient with acute monoblastic leukemia].

Although cardiac infiltration is common in advanced stage of acute leukaemia, it is not usually diagnosed at life and it is extremely rare for it to become pseudotumoral. A 25-years-old patient with an acute monoblastic leukaemia who had a leukaemic infiltration which affected the main part of the left ventricle at the time of diagnosis, is referred. The heart infiltration was detected by a two dimension echocardiography. In spite of a massive infiltration, heart failure was not present and the left ventricle's ejection fraction was 50%. Even though chemotherapy was administered, the patient died four days after diagnosis due to septic shock of respiratory origin. The most relevant autopsy finding was a widespread pseudotumoral infiltration of the left ventricle, the back side of the right ventricle and the interventricular wall. The pseudotumoral infiltration of the heart by acute leukaemia is uncommon and must be differentiated from granulocytic sarcoma. The usefulness of the different diagnostic procedures is discussed.

Adult↗

[Analysis of the mechanism of trophoblast infiltration].

A cytotrophoblast (CT) infiltrates into the stroma, forming an extravillous trophoblast (EVT) in the placenta early in gestation and the phenomenon is strictly controlled, differing from the infiltration of cancer cells. The expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), which deeply involve infiltrative metastasis of cancer, and the reactivity to transforming growth factor beta 1 (TGF beta 1), which controls the expression of these MMPs and inhibits the growth of epithelial cells, were investigated in CT derived from villi at normal gestational week 6 (early CT) and CT derived from villi at normal gestational week 37 (full-term CT), and also the choriocarcinoma cell line BeWo (BeWo). The ability of normal epithelial cells and BeWo cells to proliferate and infiltrate were evaluated in vitro by northern blotting, gelatin zymography, and invasion assay. It was revealed that early CT had a higher capacity for infiltration than full-term CT as well as BeWo. MMP2 and MMP9 appeared in the early CT, whereas only MMP9 was observed in the full-term CT. MMP2 and MMP9 were more abundantly observed in the early CT and the full-term CT rather than in BeWo. In uterine stroma-derived cells, membrane type matrix metalloproteinase (MT-MMP), which activates MMP2, was observed. These results indicated that the motility of normal villous cells was higher in the early CT than in the full-term CT. The expression of MMP2 in the early CT, which was not observed in the full-term CT, was thought to be related to this difference in motility. As for the responsiveness to TGF beta 1, which is a growth inhibiting factor for epithelial cells, the villous carcinoma cell line was insensitive to the growth inhibiting effect of TGF beta 1, but the early CT was sensitive to this effect. When TGF beta 1 was added, MMP2 and MMP9 increased in the early CT. This response was also seen in BeWo. That is, it was assured that the growth capacity was not inhibited in BeWo, but was certainly inhibited in the early CT. The overall results of these evaluations indicated that the development to EVT by infiltration of the early CT was associated with the increase in the mobility of cells caused by MMP2 and the increase in amounts of MMP2 and MMP9 caused by TGF beta 1, and the predominant inhibitory effect of TGF beta 1 on the growth of normal epithelial cells could explain why normal epithelial cells do not grow as cancer cells do.

Animals↗