Basal Cell Origin Research Articles

Live tracking of basal stem cells of the epidermis during growth, homeostasis and injury response in zebrafish.

Basal stem cells of the epidermis continuously differentiate into keratinocytes and replenish themselves via self-renewal to maintain skin homeostasis. Numerous studies have attempted to reveal how basal cells undergo differentiation or self-renewal; however, this has been hampered by a lack of robust basal cell markers and analytical platforms that allow single-cell tracking. Here, we report that zebrafish integrin beta 4 is a useful marker for basal cell labelling, irrespective of the body region, stage and regenerative status. We employed Cre-loxP recombination in combination with live cell tracking of single basal clones in the caudal fin and investigated the embryonic origin and behaviour of basal cells during fish growth and homeostasis. Although most basal cells, including those in fins, became quiescent in the adult stage, genetic cell ablation showed that basal cells were reactivated to either self-renew or differentiate, depending on the injured cell type. Our study provides a simple and easy-to-use platform for quantitative in vivo imaging of basal stem cells at wider stages and under various conditions.

Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells.

SummaryExpansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.

Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells

Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs) which express core PNEC markers, ROBO receptors, migrate toward Slit2 ligand and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. Additionally, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4\u20131 and NRDP1, in primary breast cancer

BackgroundHuman epidermal growth factor receptor HER3 (ErbB3), especially in association with its relative HER2 (ErbB2), is known as a key oncogene in breast tumour biology. Nonetheless, the prognostic relevance of HER3 remains controversial. NEDD4–1 and NRDP1 are signalling molecules closely related to the degradation of HER3 via ubiquitination. NEDD4–1 and NRDP1 have been reported to contribute to HER3-mediated signalling by regulating its localization and cell membrane retention. We studied correlations between HER3, NEDD4–1, and NRDP1 protein expression and their association with tumour histopathological characteristics and clinical outcomes.MethodsThe prevalence of immunohistochemically detectable expression profiles of HER3 (n = 177), NEDD4–1 (n = 145), and NRDP1 (n = 145) proteins was studied in primary breast carcinomas on archival formalin-fixed paraffin-embedded (FFPE) samples. Clinicopathological correlations were determined statistically using Pearson’s Chi-Square test. The Kaplan-Meier method, log-rank test (Mantel-Cox), and Cox regression analysis were utilized for survival analysis.ResultsHER3 protein was expressed in breast carcinomas without association with HER2 gene amplification status. Absence or low HER3 expression correlated with clinically aggressive features, such as triple-negative breast cancer (TNBC) phenotype, basal cell origin (cytokeratin 5/14 expression combined with ER negativity), large tumour size, and positive lymph node status. Low total HER3 expression was prognostic for shorter recurrence-free survival time in HER2-amplified breast cancer (p = 0.004, p = 0.020 in univariate and multivariate analyses, respectively). The majority (82.8%) of breast cancers demonstrated NEDD4–1 protein expression - while only a minor proportion (8.3%) of carcinomas expressed NRDP1. NEDD4–1 and NRDP1 expression were not associated with clinical outcomes in HER2-amplified breast cancer, irrespective of adjuvant trastuzumab therapy.ConclusionsLow HER3 expression is suggested to be a valuable prognostic biomarker to predict recurrence in HER2-amplified breast cancer. Neither NEDD4–1 nor NRDP1 demonstrated relevance in prognostics or in the subclassification of HER2-amplified breast carcinomas.

Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.

Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models

The heterogeneous nature of mammary tumours may arise from different initiating genetic lesions occurring in distinct cells of origin. Here, we generated mice in which Brca2, Pten and p53 were depleted in either basal mammary epithelial cells or luminal oestrogen receptor (ER)-negative cells. Basal cell-origin tumours displayed similar histological phenotypes, regardless of the depleted gene. In contrast, luminal ER-negative cells gave rise to diverse phenotypes, depending on the initiating lesions, including both ER-negative and, strikingly, ER-positive invasive ductal carcinomas. Molecular profiling demonstrated that luminal ER-negative cell-origin tumours resembled a range of the molecular subtypes of human breast cancer, including basal-like, luminal B and 'normal-like'. Furthermore, a subset of these tumours resembled the 'claudin-low' tumour subtype. These findings demonstrate that not only do mammary tumour phenotypes depend on the interactions between cell of origin and driver genetic aberrations, but also multiple mammary tumour subtypes, including both ER-positive and -negative disease, can originate from a single epithelial cell type. This is a fundamental advance in our understanding of tumour aetiology.

An Immunohistochemical Analysis of a Newly Developed, Mouse Monoclonal p40 (BC28) Antibody in Lung, Bladder, Skin, Breast, Prostate, and Head and Neck Cancers

Immunohistochemistry is important to the pathologist for accurate diagnosis of lung cancer. In recent studies, a rabbit polyclonal p40 (RPp40) antibody demonstrated equivalent staining versus anti-p63 in lung squamous cell carcinoma, and superior specificity because it stains a lesser percentage of lung adenocarcinoma. To develop an anti-p40 mouse monoclonal antibody (MMp40) for immunohistochemistry, and to evaluate its sensitivity and specificity in normal and neoplastic tissues, with emphasis on lung cancer. The MMp40 (BC28) antibody was developed and tested for specificity and sensitivity on normal (n = 34) and neoplastic tissues (n = 493). Staining of MMp40, p63, and RPp40 were directly compared in lung cancers, and MMp40 was evaluated in breast, bladder, skin, prostate, and head and neck cancers. Benign prostate glands and prostatic intraepithelial neoplasia were also tested in a direct comparison of MMp40 versus p63. The MMp40 provided equivalent staining versus RPp40 and p63 in lung squamous cell carcinoma, but stained a lesser percentage of lung adenocarcinoma than p63 did. The MMp40 staining was observed in a greater percentage of urothelial carcinomas, squamous and basal cell skin cancers, and head and neck cancers of squamous cell origin. No breast-infiltrating ductal carcinomas or prostatic adenocarcinomas were stained. The MMp40 expression in basal cells of prostate glands and prostatic intraepithelial neoplasia were almost identical to those of p63. The MMp40 (BC28) monoclonal antibody is a high-quality screening antibody for determining squamous cell carcinoma in lung cancers, skin cancers of squamous or basal cell origin, squamous cell head and neck cancers, and urothelial carcinomas.

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten(fl/fl)) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.

Expression of Cytokeratin Subtypes

Basaloid squamous cell carcinoma (BSCC) is rare variant of oral squamous cell carcinoma (OSCC) with predilection for upper aerodigestive tract. Although it is characterized by distinct histologic features it is often confused with conventional OSCC and other basaloid tumors. The study aims to establish differentiating features of BSCC with oral basaloid tumors using immunohistochemical (IHC) markers. This retrospective study included 34 cases, including BSCC, OSCC, and basaloid tumors. IHC staining was performed with primary antibodies against cytokeratin (CK) 19, 14, 8/18, α-smooth muscle actin (αSMA), p53, and MMP-9. A prominent CK 19, 14, and 8/18 expression was observed in BSCC as compared with basaloid tumors suggesting of basal cell origin with undifferentiated type of tumor cells. Expression of αSMA was intense in tumor cells of myoepithelial differentiation but lacked in BSCC. The intense expression of p53 and MMP-9 was noted in all basaloid malignancies. Considering standard histologic criteria in diagnosing BSCC, when in confusion with other basaloid tumors, IHC markers gain importance. Hence, enhanced expression of CK 19, 8/18, and 14 and coexistence of p53 and MMP-9 expression and negativity for αSMA suggest an accurate diagnosis of BSCC.

Does the microenvironment influence the cell types of origin for prostate cancer?

Despite several recent studies addressing the cells of origin for prostate cancer, there is still considerable discussion in the field regarding the most relevant target populations for transformation. Tissue regeneration studies have pointed to a basal cell origin for mouse and human prostate cancer. In contrast, genetically engineered mouse models demonstrate that cells within both the basal and luminal layers can initiate murine prostate cancer. Based on differences between these two approaches, we propose that further work should address the requirement for microenvironmental components such as immune or mesenchymal cells on epithelial cell types of origin for prostate cancer.

Su1942 Photodynamic Therapy Induces Apoptosis via Reactive Oxygen Species in Fluorouracil-Resistant Esophageal Squamous Cell Carcinoma Cells

mice. The tumors were K19 positive (partial), p63 positive, cyclin D1 positive, and TFF2 negative by immunohistochemistry. KRT14 mRNA was increased in tumors compared to that in forestomach and gastric epithelium, suggesting basal squamous cell origin of tumors. Conclusion; K19 positive cells can be an origin of mouse SCJ SCC. Loss of TGF beta signaling coupled with Kras mutation is critical for tumor development and invasion of SCC especially at SCJ. This model will be useful for the investigation of tumors arising at SCJ.

Su1941 Aldehyde Dehydrogenase-2 Regulates Esophageal Epithelial Cell Senescence Checkpoint Functions Activated by an Alcohol Metabolite

mice. The tumors were K19 positive (partial), p63 positive, cyclin D1 positive, and TFF2 negative by immunohistochemistry. KRT14 mRNA was increased in tumors compared to that in forestomach and gastric epithelium, suggesting basal squamous cell origin of tumors. Conclusion; K19 positive cells can be an origin of mouse SCJ SCC. Loss of TGF beta signaling coupled with Kras mutation is critical for tumor development and invasion of SCC especially at SCJ. This model will be useful for the investigation of tumors arising at SCJ.

Abstract C64: Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation

Abstract The prostate epithelial lineage hierarchy and the cellular origin for prostate cancer remain inadequately defined. We sought to utilize a lineage tracing approach to define the epithelial lineage hierarchy in the prostate. A previously reported K14-CreER transgenic mouse line was bred with a fluorescent reporter line to specifically label the prostate basal cell lineage. In parallel, the prostate luminal cell lineage was labeled with fluorescence using a novel K8-CreERT2 transgenic mouse line generated in our own lab. Using this lineage tracing approach, we show that adult rodent prostate basal and luminal cells are independently self-sustained in vivo. We then sought to characterize the cells of origin for prostate cancer in the context of loss of function of Pten, which occurs frequently in primary and advanced human prostate cancer. We bred the K14-CreER and K8-CreERT2 mouse lines with Ptenfl/fl mice separately so that Pten expression can be disrupted specifically in prostate basal and luminal cells, respectively. Disrupting Pten in either lineage led to prostate cancer initiation. However, the cellular composition and onset dynamics of the resulting tumors are distinctive. Prostate luminal cells are more responsive to Pten null-induced mitogenic signaling. In contrast, basal cells are resistant to direct transformation. Instead, loss of Pten activity induces the capability of basal cells to differentiate into transformation-competent luminal cells. These studies suggest that deregulation of the normal prostate epithelial differentiation program is a critical step for initiation of human prostate cancer with a basal cell origin. Furthermore, suppressing signaling pathways that induce basal-luminal differentiation may provide an efficient approach to prevent prostate cancer initiation. Citation Format: Nahyun Choi, Boyu Zhang, Li Zhang, Michael Ittmann, Li Xin. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C64.

Adult Murine Prostate Basal and Luminal Cells Are Self-Sustained Lineages that Can Both Serve as Targets for Prostate Cancer Initiation

The prostate epithelial lineage hierarchy and the cellular origin for prostate cancer remain inadequately defined. Using a lineage-tracing approach, we show that adult rodent prostate basal and luminal cells are independently self-sustained in vivo. Disrupting the tumor suppressor Pten in either lineage led to prostate cancer initiation. However, the cellular composition and onset dynamics of the resulting tumors are distinctive. Prostate luminal cells are more responsive to Pten null-induced mitogenic signaling. In contrast, basal cells are resistant to direct transformation. Instead, loss of Pten activity induces the capability of basal cells to differentiate into transformation-competent luminal cells. Our study suggests that deregulation of epithelial differentiation is a critical step for the initiation of prostate cancers of basal cell origin.

Two Cases of Neoplasia of Basal Cell Origin Affecting the Axillary Region in Anseriform Species

Neoplasms of the skin are occasionally seen in domestic birds but are uncommon in nondomestic birds. An 8-year-old male hooded merganser (Lophodytes cucullatus) was presented with bilateral axillary ulcerative lesions that improved but did not resolve with empiric antibiotic and antifungal therapy. Skin biopsies were taken, and bilateral feather folliculomas were diagnosed on histopathologic examination. The duck was euthanatized because of the poor prognosis. A 9-year-old Indian runner duck (Anas platyrhynchos) was presented with an ulcerative lesion, with pseudomembrane and serocellular crust affecting the axillary region. This mass was diagnosed as a basosquamous carcinoma. The mass was surgically excised, and no recurrence was observed. Feather folliculomas are usually considered benign neoplasms in domestic birds and may be primarily ulcerative, exudative, bilateral, and symmetric in location. Basosquamous carcinoma may have a similar gross appearance. It is unknown if the axillary region may be an area with increased incidence of neoplasia in birds. This appears to be the first report of feather folliculoma and basosquamous carcinoma in Anseriforme species. Feather folliculomas and other neoplasms, such as basosquamous carcinoma, should be considered as a differential diagnosis in ulcerative or proliferative skin lesions in birds.

Genetic origin and proportion of basal plate surface-lining cells in normal and abnormal pregnancies

The human placenta is a transient organ, the villous surface of which is in direct contact with the maternal circulation during pregnancy. Thus, the syncytiotrophoblast and the basal plate-lining cells are considered continuous with the endothelial layer of the maternal vasculature. Two types of cells are found on the surface of the basal plate: trophoblasts (of fetal origin) and endothelial cells of putative maternal origin. Histologic abnormalities have been described in the basal plate of the placenta obtained from patients with preeclampsia and intrauterine growth restriction. Moreover, endothelial cell dysfunction and intravascular inflammation are key features of preeclampsia. The objectives of this study were to: (1) determine the origin of the endothelial cells located in the basal plate surface of the placenta (from male fetuses); and (2) analyze the relative proportion of the intervillous surface of the basal plate occupied by trophoblasts and endothelial cells. Immunohistochemistry and morphometry were performed in placentas from women in the following clinical groups: (1) normal-term pregnancies (n = 15); (2) severe preeclampsia at term (n = 15); (3) small-for-gestational-age (SGA) neonates delivered at term (n = 15); (4) preterm deliveries (<37 weeks) without inflammation (n = 5); and (5) preterm preeclampsia (n = 5). Laser capture microdissection and polymerase chain reaction were used to determine the allelic pattern of the amelogenin gene of the endothelial cells on the intervillous surface of the basal plate. Our results showed that: (1) the endothelial cells lining the basal plate in placentas of male fetuses were uniformly of maternal origin; and (2) in placentas from uncomplicated pregnancies, the median proportion of trophoblasts and endothelial cells covering the surface of the basal plate were 27.7% and 46.5%, respectively. The remaining area of the intervillous surface of the basal plate was composed of fibrin and anchoring villi. Of interest, placentas from women who delivered an SGA neonate had a higher proportion of trophoblasts and a lower proportion of endothelial cells lining the basal plate than those from normal pregnancies (P < .05). The same tendency was observed in placentas from patients with preeclampsia. This study demonstrates that endothelial cells of maternal origin cover the intervillous surface of the basal plate of the placenta, along with trophoblasts of fetal origin. The proportion of this surface lined by trophoblasts is greater in placentas from SGA and preeclampsia than in normal pregnancy. We propose that this change reflects a compensatory mechanism whereby the basal plate surface covered by injured endothelial cells is replaced by trophoblasts or results from a failure of trophoblastic involution in abnormal pregnancies. Our observations also suggest that the lining of the basal plate can provide information about the pathology of endothelial cells in complications of pregnancy.

Genetic origin and proportion of basal plate surface cells in normal and abnormal pregnancies

The basal plate of the placenta is the floor of the intervillous space. The cellular constituents of the basal plate surface that are in direct contact with maternal blood include trophoblasts (TB; of fetal origin) and endothelial cells (EC) whose origin (fetal or maternal) is unknown. This study was conducted to 1) determine the origin of these EC; and 2) to assess the relative proportion of TB and EC covering the intervillous surface of the basal plate in placentas from normal and preeclamptic pregnancies. Placentas from patients with normal term gestations (n = 9) and preeclampsia (n = 10) were included. Five sections of the basal plate were obtained from the central, paracentral and peripheral regions of each placenta. Double immunohistochemistry (vimentin: EC and cytokeratin 7: TB) and image analysis were performed. Seven placentas of male fetuses were used to evaluate the origin of the EC. Genomic DNA isolated from laser microdissected EC was subjected to PCR for sex typing. Data were analyzed using non-parametric statistics. 1) The median proportion of TB and EC covering the basal plate surface in normal placentas was 8% (range 6.5-17.6%) and 13.6% (range: 4.4-24.6%), respectively; 2) the median TB/EC ratio was 0.8 (range: 0.3-4); 3) in preeclampsia, the basal plate surface showed a higher proportion of TB than those from normal pregnancies (median: 17.6%, range: 5.9-29.2%, p = 0.04); 4) a trend towards a lower proportion of EC in preeclampsia was observed; and 5) EC covering the basal plate were of maternal origin. 1) For the first time, EC lining the intervillous space surface of the basal plate have been identified to be of maternal origin; and 2) preeclampsia is associated with an excess of TB covering the surface of the basal plate.

Merkel Cells, Normal and Neoplastic: An Update

Merkel cells (MC) occur in the basal epidermal layer, hair follicles, and oral mucosa, as complexes with sensory axons. The axons transduce slowly adapting type I mechanoreception, and MC modulate their sensitivity. MC also determine and maintain the 3-dimensional epidermal structure. They have neuroendocrine granules, rigid spinous processes, and desmosomal junctions with each other and with keratinocytes. Rare MC are dermaWl. Current evidence supports a basal cell origin. Merkel cell carcinomas (MCC) occur mostly in sun-exposed skin in old age. Trabecular, intermediate, or small cell in pattern, MCC have neuroendocrine granules, intercellular junctions, rigid spinous processes, and a paranuclear collection of intermediate filaments staining for cytokeratin 20. Most MCC behave indolently, but those with the small cell pattern, and some with the intermediate pattern, are aggressive and rapidly fatal.

Changes in matrix metalloproteinases and their endogenous inhibitors during tumor progression in the uterine cervix.

To study the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cervical tumorigenesis, we analyzed 70 cervical tissue specimens that included 15 low-grade squamous intraepithelial lesions (SILs), 20 high-grade SILs, 25 squamous cell carcinomas (SCCs) and 10 specimens of normal cervical tissue. The gelatinolytic activity of MMP-9 and MMP-2 was determined by zymographic analysis. The expression of MMP-9 and MMP-2 and TIMP-1 and TIMP-2 was determined by immunohistochemistry. All the samples had 72/66 kDa gelatinase activity; 92 kDa gelatinase activity was detected only in high-grade SILs and SCCs. Immunohistochemical analysis showed weak positivity for MMP-2 in normal cervical epithelium and low-grade SILs. However, high-grade SILs and SCCs showed intense cellular and stromal reactivity for MMP-2 and MMP-9. For TIMP-1 and TIMP-2, normal cervical epithelium and low-grade SILs showed intense immunostaining, >50% of high-grade SILs showed positivity, and 95% of SCCs showed intense stromal and cellular reactivity. Increase in the relative activity of these gelatinases and enhanced immunostaining for MMPs and TIMPs with tumor progression suggest that they may play a crucial role in cervical cancer progression. A significant association between stage of the lesion and expression of MMPs and TIMPs ( P<0.01) was found. Immunohistochemical studies indicate that these MMPs may be of basal cell origin in cervical tissue, although the mechanism of their upregulation is not clearly understood.

A possible extratubular origin of epididymal basal cells in mice.

The origin of basal cells in mouse epididymis was examined by counting the numbers of basal cells, intratubular mitotic figures and peritubular cells during development of the epididymis. Putative precursors of basal cells were labelled with bromodeoxyuridine and the nuclei of daughter cells were examined. Histochemical localization of cytokines was performed to gauge their involvement in migration of basal cell precursors from extratubular sources. The results indicate that basal cells may arise from extratubular sources as: (i) there was a decrease in the number of mitotic figures as the number of basal cells increased; (ii) no mitotic figures were observed in the base of the epithelium; (iii) the increase in the number of peritubular cells did not parallel the number of basal cells in all epididymal regions; (iv) division of epithelial cells into daughter cells was circumferential and not radial; (v) bromodeoxyuridine-labelled basal cell nuclei were mostly not found in the vicinity of labelled principal cell nuclei and vice versa; and (vi) the percentage of labelled basal cell nuclei was higher than that of the other cells, which is indicative of their arrival from a more highly labelled pool. In addition, no age-dependent correlation was noted between any of the cytokines tested and appearance of basal cells in the epithelium, and basal cells expressed intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), which provides further evidence of a relationship between basal cells and immunocytes. If basal cells have an immunological function, failure of their recruitment into the epididymal epithelium at about the time of puberty may have repercussions for immunological protection of spermatozoa and, ultimately, for fertility in the adult.