Stromal-epithelial interactions in breast cancer.
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Animals↗
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Results for “Stromal-epithelial interactions”
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Stromal-epithelial interactions in normal and neoplastic mammary gland.
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Animals↗
Prostatic maldevelopment in the prune belly syndrome: a defect in prostatic stromal-epithelial interaction.
The prune belly syndrome consists of a triad of abdominal wall musculature deficiency, cryptorchidism and urinary tract anomalies. A rarely described but fairly constant component of the syndrome is the lack of development of the epithelial elements of the prostate. We wish to suggest that this is a further expression of a postulated arrest in mesenchymal development responsible for other features of the syndrome.
Abdominal Muscles↗
Stromal-epithelial interactions in normal and abnormal prostatic development.
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Androgens↗
Stromal regulation of epithelial function.
Stromal influences upon epithelia are part of a continuum of cellular interactions that begins at fertilization and extends into adulthood. In parenchymal organs, the most thoroughly characterized interactions have been those that occur during development between mesenchyme, embryonic stroma, and epithelium. Mesenchyme is essential for epithelial proliferation, morphogenesis, and differentiation. Hormones affect stromal-epithelial interactions, and in some cases, steroid hormones may produce their effects on the epithelium indirectly, acting via the mesenchyme. In many adult organs the epithelia continually proliferate and differentiate and consequently may be considered developing systems within the mature organism. This is especially true in organs with a rapidly renewing epithelium, such as the intestine, and in organs that have cycles of functional activity, such as those of the female reproductive system. The mechanisms by which stroma affects epithelial structure and function are not well understood. Current models of how signaling may be accomplished include transmission via diffusible substances, via the extracellular matrix (ECM), and via direct cell-cell contact. Growth factors and organ-specific paracrine factors are candidates for stromal cues that affect the epithelium in some systems. Components of the ECM appear to play a role in permissive interactions and may affect epithelial function by changing cell shape or by binding ECM to the cell surface integrin receptors. Signaling via direct stromal-epithelial contact may be accomplished via interactions between complimentary cell surface adhesion molecules. The importance of stromal-epithelial interactions is reemphasized by several models of carcinogenesis that suggest that perturbations in these interactions may be involved in tumor progression.
Adult↗
Epithelial component of host-tumor interactions in the orthotopic site preference of a mouse mammary tumor.
Mouse mammary tumors grow preferentially upon transplantation into intact mammary glands compared to cleared mammary fat-pads. Both sites provide stroma of the orthotopic site, but the latter lacks epithelial elements. If epithelium from enzymatically dissociated normal mammary glands is added to the tumor cells prior to injection into cleared fat-pads, tumor growth is comparable to that seen in intact mammary fat-pads. The growth-enhancing effects of normal mammary cells are not duplicated by normal kidney or liver cells. These results demonstrate that epithelial-epithelial interactions, as well as stromal-epithelial interactions, are associated with the enhanced growth of mammary tumor cells transplanted into orthotopic sites. The results also suggest that enhancement of tumor growth does not require intact tissue architecture.
Animals↗
Decoding regional keratinization in human oral mucosa through high-resolution spatial transcriptomics.
Oral mucosa exhibits region-specific keratinization, essential for periodontal health, yet the spatial and molecular mechanisms driving these differences remain poorly understood. This study aimed to generate a high-resolution spatial transcriptomic atlas of the human oral mucosa around the mucogingival junction, to reveal stromal-epithelial interactions, that distinguish keratinized from non-keratinized programs. Formalin-fixed paraffin-embedded specimens from the mucogingival junction area of two healthy donors were analyzed with the 10 × Genomics Visium HD platform, yielding two keratinized and two non-keratinized regions. Spatial clustering, pseudotime trajectory inference, cell-type integration with a single-cell reference, and ligand-receptor network analysis were applied to delineate epithelial and stromal compartments. Sixteen reproducible clusters, recapitulating tissue architecture, were identified and revealed distinct transcriptional signatures, distinguishing gingiva from lining mucosa. Pseudotime analysis revealed bifurcating epithelial lineages, originating from a shared basal progenitor layer into keratinized and non-keratinized programs. Gingival keratinization was driven by stromal collagen ligands (COL1A1, COL1A2, COL6A1, COL6A2) engaging epithelial receptors (CD44, SDC1), further reinforced within the epithelium by desmosomal adhesion via DSG1-DSC2/3. Gingival keratinization emerges from integrated stromal collagen signaling and epithelial adhesion. This spatially resolved framework advances understanding of oral mucosal specialization and provides a foundation for biologically guided regenerative therapies.
Humans↗
Etiology and disease process of benign prostatic hyperplasia.
The natural history of benign prostatic hyperplasia (BPH) involves two phases. The first, or pathological phase of BPH, involves two stages, termed microscopic and macroscopic BPH, neither of which produces symptomatic clinical dysuria. Nearly all men throughout the world will eventually develop microscopic BPH if they live long enough. In only about one-half of the men with microscopic BPH, however, will microscopic BPH grow to produce a macroscopic enlargement of the gland (i.e., macroscopic BPH), suggesting that additional factors are required for the progression of microscopic to macroscopic BPH. Several theories have been proposed to explain the etiology of the pathological phase of BPH. The major theories include the hypotheses that pathological BPH is due to 1) a shift in prostatic androgen metabolism that occurs with aging, which leads to an abnormal accumulation of dihydrotestosterone, thus producing the enlarged prostate (i.e., DHT hypothesis), 2) a change in the prostatic stromal-epithelial interact that occurs with aging, which leads to an inductive effect on prostatic growth (i.e., embryonic reawakening theory), or 3) an increase in the total prostatic stem cell number and/or an increase in the clonal expanding of the stem cells into amplifying and transit cells that occurs with aging (i.e., stem cell theory). The second, or clinical phase of BPH, involves the progression of pathologic BPH to clinical BPH in which the patient develops symptomatic dysuria. Only about one-half the men with macroscopic BPH progress to clinical BPH. Although the macroscopic enlargement of the prostate is a necessary condition for the development of clinical BPH, this enlargement is usually not sufficient by itself for the progression of pathologic BPH to clinical BPH. The etiology of the progression of pathological BPH to clinical BPH requires additional factors (e.g., prostatitis, vascular infarct, tensile strength of the glandular capsule, etc.). A successful treatment for clinical BPH, therefore, does not necessarily require either the prevention or elimination of all degrees of pathologic BPH. Instead, what is needed is a therapy to prevent or reverse the progression of pathologic BPH to the clinical disease.
Adult↗
Colonic pericryptal fibroblasts. Differentiation pattern in embryogenesis and phenotypic modulation in epithelial proliferative lesions.
Experimental evidence has shown that fetal gut mesenchymal cells can modulate epithelial cell differentiation. It is postulated that reciprocal stromal-epithelial interactions in the digestive tract are maintained beyond embryonic life. The mature colonic mucosa contains pericryptal fibroblasts (PCF), a stromal cell type exhibiting smooth muscle morphological features, which are thought to regulate the growth and differentiation of adjacent epithelial cells. Using an antibody directed at alpha-smooth muscle actin, which is constantly expressed in smooth muscle cells, we performed an immuno-histochemical study on human embryonic tissues to assess PCF differentiation during development. PCF expressing alpha-smooth muscle actin were first detected around the 21st week of gestation, at the bases of the crypts; the number of differentiated PCF increased then progressively, in synchrony with epithelial proliferation, to achieve at birth the characteristic distribution found in adults. We analyzed a series of non-malignant and malignant epithelial proliferative lesions of the adult colon by the same technique. Only sparse immunoreactive PCF were observed in 10/10 pure tubular adenomas, whereas in 11/11 villous adenomas immunoreactive PCF were consistently found bordering proliferative epithelia. Interestingly, 3/5 papillary adenomas, associated with areas of moderate to marked dysplasia, demonstrated foci of multilayered immunoreactive PCF. In 14/14 carcinomas examined, PCF were no longer recognizable; stromal cells expressing variable amounts of alpha-smooth muscle actin, constituting the desmoplastic reaction, were constantly present. These observations establish immunohistochemically a smooth muscle phenotypic feature of PCF, which is acquired at mid-gestation, and the ability of PCF to proliferate in conjunction with some epithelial neoplasias. These findings might help to clarify the histogenesis of PCF and to improve our understanding of the mesenchymal-epithelial interactions suspected to operate during organogenesis as well as benign and malignant neoplastic conditions.
Actins↗
Serum-free culture of stromal and functionally polarized epithelial cells of guinea-pig endometrium: a potential model for the study of epithelial-stromal paracrine interactions.
Stromal and glandular epithelial (GE) cells were isolated from guinea-pig endometrium and growth to near confluency (6-8 days) in primary culture on plastic surfaces in a serum-supplemented medium (SSM). The stromal cells were subcultured on plastic dishes and maintained for 72 h in SSM. Then SSM was replaced by a chemically defined medium (CDM) and the stromal cells grown to confluency (5-7 days). The GE cells were subcultured in CDM, on a basement membrane matrix (Matrigel) applied to permeable Millicell-PC filters, and grown to confluency (5 days). Homogeneity of the subcultured endometrial cell populations was ascertained immunocytochemically. The filter-cultured GE monolayers were polarized morphologically, and displayed epithelial-specific specialized structures. These monolayers had functional tight junctions as verified by a measurable transepithelial resistance. The subcultured cell populations were distinguished by an analysis of their cellular and secretory proteins after labelling with [35S]-methionine and analysis by polyacrylamide gel electrophoresis. The filter-cultured GE monolayers allowed identification of the proteins released vectorially in the apical or the basal secretory compartment, thus demonstrating the functional polarization of GE cells in this bicameral culture system. Within the defined conditions of this culture system, the paracrine factors released by the two endometrial cell populations as well as the interplay of stromal-epithelial interactions and ovarian hormones could be investigated.
Animals↗
Detection and partial purification of a potent mitogenic factor for human thyroid follicular cells.
Normal adult human thyroid follicular cells have an extremely limited proliferative capacity in vitro. No previously studied mitogen, including thyrotropin (TSH) or epidermal growth factor (EGF), has in our hands resulted in a significant improvement over the 3-4% nuclear [3H]thymidine pulse-labelling index (LI) obtainable with 10% fetal calf serum. Here we report the detection in the conditioned medium from a sub-clone of NIH3T3 fibroblasts of a mitogenic activity capable of increasing this response up to 10-fold, to an LI of over 20%, together with an even greater relative stimulation of mitotic activity. Preliminary characterisation has excluded EGF and TGF alpha, and demonstrated that the activity is bound reversibly by heparin-Sepharose, thus pointing to a member of the heparin-binding fibroblast- or hepatocyte-growth factor families. This material should have wide practical application in facilitating primary culture of follicular cells, and may reveal new mechanisms of stromal-epithelial interaction regulating normal and neoplastic thyroid growth in vivo.
Cell Division↗
Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis.
Prostate cancer selectively metastasizes to the axial skeleton to produce osteoblastic lesions, which suggests that bidirectional paracrine interactions exist between prostate cancer and bone cells. To evaluate the role of tumor-stromal cell interaction and stromal-specific growth factors in prostate cancer growth and dissemination, we coinoculated nontumorigenic human prostate cancer cells (LNCaP) and various tissue-specific fibroblasts subcutaneously in athymic mice. LNCaP tumors were induced most consistently by human bone fibroblasts (62%), followed by two prostate fibroblast cell lines (31% and 17%), but not by lung, kidney, or embryonic 3T3 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. Immunohistochemical and biochemical techniques confirmed the human prostate component of these tumors and were paralleled by elevations in serum prostate specific antigen. In vitro mitogenic assays revealed a two-to three-fold bidirectional stimulation between LNCaP and bone or prostate fibroblast conditioned media, but not lung, kidney, or 3T3 fibroblast conditioned media. A novel method developed to deliver concentrated bone or prostate fibroblast conditioned media in vivo using a slowly absorbed matrix (gelfoam) also induced tumor formation, emphasizing the importance of fibroblast growth factors in LNCaP tumor formation. Northern analysis identified the stromal compartment as the primary source of extracellular matrix (collagen, fibronectin), while only LNCaP cells expressed transforming growth factor alpha. Although LNCaP and stromal cells express basic fibroblast growth factor (bFGF), the bidirectional paracrine-mediated mitogenic activity between these cells is not inhibited by anti-bFGF antibodies, suggesting that other undefined growth factors may be involved in stimulating LNCaP growth. These observations illustrate the importance of stromal-epithelial interaction in prostate tumor growth and suggest that extracellular matrix and paracrine-mediated growth factors play a role in prostate cancer growth and metastasis.
Androgens↗
Differentiation of rat intestinal epithelial cells is induced by organotypic mesenchymal cells in vitro.
Stromal-epithelial interaction is a potent driving force in the developing intestinal mucosa which ensures tissue specific cellular differentiation. The mechanisms involved are relevant to tissue renewal in adult organs yet they have not been elucidated because of the lack of appropriate in vitro models. In this study, we have investigated the interaction between intestinal mesenchymal and epithelial cells at the cellular level in vitro. Fetal rat intestinal epithelial cell colonies explanted in vitro on the 15th day of gestation, which failed to mature in plain monocultures, were reassociated in coculture with three different types of mesenchyme:fetal skin, gastric and intestinal mesenchyme. Only fetal epithelial cells cocultured with intestinal (homologous) mesenchyme acquired definite signs of differentiation within three to six days. These primitive epithelial cells were shown by electronmicroscopy to become highly polarized, connected by tight junctions and covered with a regular brush border. Three brush border enzymes were strongly expressed in homologous cocultures and their activity was sensitive to dexamethasone. In contrast, fetal epithelial cells cocultured with skin or stomach derived mesenchyme under identical conditions failed to differentiate in vitro: they remained flat, unpolarised and expressed only low enzyme activity. The unique potential of the small intestinal mesenchyme to promote intestinal epithelial differentiation is discussed.
Animals↗
Role of stroma in oestrogen-induced epithelial proliferation.
To examine the role of stromal-epithelial interactions in the response of epithelial cells to oestrogens, tissue recombinations were prepared with epithelium (E) and stroma (S) from the vagina (V) and urinary bladder (BL), that is between oestrogen target tissues (VS and VE) and non-target tissues (BLS and BLE). Following 3 weeks of growth in intact female hosts, ovariectomy was performed and 1 week later the hosts subjected to various hormonal treatments. Whereas homotypic vaginal tissue recombinations (VS+VE) exhibited epithelial cornification and mucification (cycling), this activity was not observed in homotypic bladder recombinants (BLS+BLE) or in heterotypic tissue recombinants between vaginal and bladder tissues (VS+BLE and BLS+VE). In BLS+VE recombinants the epithelium remained atrophic and failed to respond to exogenous oestrogen alone or in combination with progesterone. This lack of hormonal responsiveness of vaginal epithelium was completely reconstituted when the epithelium of BLS+VE recombinants was recovered and reassociated with fresh vaginal stroma (VS). Examination of epithelial proliferative activity ([3H]thymidine labelling index) demonstrated a marked oestrogen-induced increase in epithelial proliferation in VS+VE recombinants. BLS+BLE recombinants were unresponsive to oestrogen as were recombinants composed of BLS+VE. However, when bladder epithelium was grown in association with vaginal stroma (VS+BLE) the epithelium exhibited an 8-fold oestrogen-induced increase in labelling index over oil-treated specimens. The lack of an oestrogen-induced proliferative response of vaginal epithelium in BLS+VE recombinants was reversed when the vaginal epithelium of these recombinants was recovered and reassociated with fresh vaginal stroma. These results indicate that the effects of oestrogen and progesterone on both epithelial differentiation and proliferation are critically dependent upon the appropriate stromal environment.
Animals↗
Retinal pigment epithelium-stromal interactions modulate hyaluronic acid deposition.
Hyaluronic acid (HA) is a major component of the extracellular matrix (ECM) and is particularly prominent in various structures of the eye. Choroidal mesenchymal fibroblasts (CHM) and fetal retinal pigment epithelial (fRPE) cells were cultured individually and in cocultivation, as a paradigm for ocular stromal-epithelial interactions. Such interactions are thought to be a key mechanism for the modulation of the ECM and of HA deposition in the region of Bruch's membrane and related structures. In cocultivation, increased levels of HA production were observed, more than the sum of the two cell types grown individually. Conditioned medium from fRPE cultures placed over CHM cells was able to enhance production in such cells several-fold, demonstrating that cell-cell contact was not needed for this enhanced production. On the other hand, when conditioned medium from CHM fibroblasts was added to the fetal RPE cells, no increase in HA production was observed. A soluble HA-stimulating factor apparently released by fRPE cells in a paracrine manner enhanced HA production in CHM cells. The fRPE cell-conditioned media was unable to exert this effect on the fRPE cells themselves. The fRPE cells may lack the appropriate receptor. Alternatively, they may not have the biosynthetic machinery for augmented HA production.
Cell Communication↗
Kinetic and morphometric responses of heterogeneous populations of experimental breast cancer cells in vivo.
Although the hormone responsiveness of some breast cancers is well known, the differential sensitivity of tumor cell subpopulations to hormonal effects is not well established. These experiments were designed to address this issue using the hormone-responsive N-nitrosomethylurea-induced rat mammary tumor. Rats bearing these tumors were randomly assigned to no treatment, 7-day castration, and 7-day castration followed by 1-, 3-, 7-, and 10-day treatment with estradiol benzoate (5 micrograms) and perphenazine (1 mg) to stimulate prolactin release. Under these conditions, the proportion of different cell populations was estimated with morphometric analysis, while their replicative activity was assessed using [3H]thymidine autoradiography. In tumors of intact rats the fractions of glandular epithelial, myoepithelial, and nonepithelial cells were 88.2%, 3.8%, and 8.0%, respectively. All cell types manifested a similar kinetic response to our hormonal treatments characterized by a drastic decline in the labeling index after castration followed by a progressive increase with hormone repletion which peaked on Day 7 of treatment. The magnitude of the response was, however, greater in the epithelial components of the tumor (glandular and myoepithelial cells), where the peak labeling indices significantly exceeded those observed in the tumors of control intact rats. Castration reduced the proportion of glandular cells while increasing the fractions of myoepithelial and nonepithelial cells. Furthermore, castration reduced the volume of the glandular-epithelial cells by 35%, which accounted for approximately half of the overall tumor volume reduction induced by ovariectomy. These alterations in tumor morphology were partially reversed by hormone repletion. These results underscore the exquisite hormonal sensitivity of different cellular counterparts of this experimental breast cancer with regard to both kinetic and morphological characteristics. They also provide support for stromal-epithelial interaction in the hormonal modulation of breast cancer growth.
Animals↗
Quantitative determination of prostatic epithelial and stromal hyperplasia by a new technique. Biomorphometrics.
Recent studies of neonatal and pathologic growth of the prostate have postulated the possible importance of stromal-epithelial interaction in the control of prostatic growth. To allow further analysis of the possible importance of this interaction, a new technique has been developed that permits quantification of the total number of stromal and epithelial cells in the prostate gland. This technique has been termed biomorphometrics and is a combination of standard morphometric and biochemical methodology. This method has been applied to analyze the hormonal response of the stromal and epithelial cells of the rat ventral prostate.
Animals↗
Effect of aging on kinetic parameters of 5 alpha-reductase in epithelium and stroma of normal and hyperplastic human prostate.
Altered 5 alpha-dihydrotestosterone (DHT) metabolism and stromal-epithelial cell interactions are two factors hypothesized to explain the development of benign prostatic hyperplasia (BPH). Furthermore, the development of BPH is clearly age dependent. Therefore, we studied the age-dependent alteration of 5 alpha-reductase, the enzyme that catalyzes the irreversible conversion of testosterone to DHT in epithelium and stroma of the human prostate. For this purpose kinetic parameters [Km Vmax] of 5 alpha-reductase were determined separately in epithelium and stroma of normal prostatic tissue (NPR) from 5 and BPH tissue from 20 men, and the results were correlated with the age of the donors (15-86 yr). The mean Km in epithelium [NPR, 14.3 +/- 1.8 (+/- SE); BPH, 29.5 +/- 2.7 nmol/L] was significantly (P less than 0.0001) lower than that in stroma (NPR, 78.4 +/- 8.5; BPH, 185.8 +/- 13.6 nmol/L). The mean Vmax in epithelium [NPR, 23.8 +/- 3.9 (+/- SE); BPH, 27.9 +/- 3.0 pmol/mg protein.h] was significantly (P less than 0.0001) lower than that in stroma (NPR, 68.3 +/- 4.4; BPH, 173.8 +/- 12.2 pmol/mg protein.h). The DHT-forming index (Vmax/Km) in NPR epithelium [1.6 +/- 0.2 (+/- SE)] was significantly (P less than 0.01) higher than that in NPR stroma (0.9 +/- 0.1), while in BPH the DHT-forming index was nearly identical in epithelium (1.1 +/- 0.1) and stroma (1.0 +/- 0.1). The Km values in epithelium and stroma both correlated positively (P less than 0.01) with age, but the Vmax values correlated positively with age (P less than 0.0001) only in stroma. The DHT-forming index decreased significantly with age in epithelium (P less than 0.01), but remained constant in stroma. These results indicate that there is a nonuniform age-dependent alteration of Km and Vmax in epithelium and stroma of the human prostate independent of the presence of BPH, which might have an impact on the conversion rate of testosterone to DHT with advancing age.
Adult↗