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PubMed1986

[Analysis of normal human endometrial stroma cells--identification of proliferating cells in the human endometrial stroma in the late secretory phase by immunohistochemistry using various monoclonal antibodies to human leukocytes combined with 3H-thymidine autoradiography].

Combined immunohistochemical methods using the various monoclonal antibodies to human leucocytes and incorporation of radiothymidine in vitro were applied to human endometrium during the late secretory phase. It was clarified from this study that endometrial granulocytes frequently incorporated radiothymidine but no stromal fibroblast did during the mid and late secretory phase. Endometrial granulocytes carried leucocyte common antigen, and they also reacted to Leu 9 and OKT10 antibodies. Endometrial granulocytes are probably a type of migrating cells of bone marrow origin.

Adult↗
PubMed2004

Histological categorisation of fibrotic cancer stroma in advanced rectal cancer.

BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development--namely, that a desmoplastic reaction can favour either the host or the tumour--it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. METHODS: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. RESULTS: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.

Adenocarcinoma↗
PubMed2001

Reactive stroma in prostate cancer progression.

PURPOSE: The development of an altered stromal microenvironment in response to carcinoma is a common feature of many tumors. We reviewed the literature describing characteristics of reactive stroma, how reactive stroma affects cancer progression and how carcinoma regulates reactive stroma. Moreover, we present a hypothesis of reactive stroma in prostate cancer and discuss how the biology of reactive stroma may be used in novel diagnostic and therapeutic approaches. MATERIALS AND METHODS: An extensive literature search was performed to review reports of the general features of wound repair stroma, general stromal responses to carcinoma, and stromal biology of normal and prostate cancer tissues. These studies were analyzed and a reactive stroma hypothesis in prostate cancer was developed. RESULTS: Modifications to the stroma of breast, colon and prostate tumors parallel the generation of granulation tissue in wound repair. These changes include stromal cell phenotypic switching, extracellular matrix remodeling and angiogenesis induction. Therefore, it is predicted that a modified wound healing response induces the formation of reactive stroma in cancer to create a tumor promoting environment. Based on its role in wound repair and its over expression in prostate cancer, transforming growth factor-beta stands out as a potential regulator of reactive stroma. CONCLUSIONS: Reactive stroma in prostate cancer and granulation tissue in wound repair show similar biological responses and processes that are predicted to promote cancer progression. Further identification of specific functional and regulatory mechanisms in prostate cancer reactive stroma may aid in the use of reactive stroma for novel diagnostic and therapeutic approaches.

Disease Progression↗
PubMed2003

Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer.

Extensive scientific literature data point to reciprocal interactions between prostate stromal cells and prostate cancer cells that likely regulate tumor progression. To investigate whether these intratumoral-reactive stromal cells in human prostate cancer are predictive of survival, tumor stroma volume and specific stroma markers were quantitated by using tissue microarrays (index tumors of 847 patients), and the results were analyzed relative to the recurrence-free survival data set for these patients. Tumor tissue was evaluated with Masson's trichrome stains and by immunohistochemistry with antibody probes to smooth muscle alpha-actin, desmin, vimentin, pro-collagen type I, and calponin. The relative volume of intratumor stroma (5% stroma, grade 0; 5-15%, grade 1; 15-50%, grade 2; >50%, grade 3) and the expression index of stromal marker (staining intensity grade x percentage of positive cells per field) were quantitated and analyzed. Interpretable data were obtained from 545 patients. Statistical analysis of the survival data set showed that the volume of reactive stroma in the tumor was a significant predictor of disease-free survival. Stroma volume was most optimal as an independent predictor in tumors containing stroma, defined as Gleason 7 and lower grades. Of interest, tumors with either little to no stroma or tumors with abundant stroma each showed reduced recurrence-free survival. For specific stromal markers, reduced desmin and smooth muscle alpha-actin were hallmarks of cancer-associated reactive stroma relative to normal fibromuscular stroma. Quantitative analysis of desmin and smooth muscle alpha-actin expression showed both to be significant and independent predictors of recurrence-free survival. This is the first study to demonstrate that nonepithelial-reactive stroma elements in prostate cancer tumors can be used as prognostic indicators. These data also add to the concept that tumors are not purely epithelial and the tumor-reactive stroma must be considered an important biological component of the cancer.

Actins↗
PubMed1996

Cryopreserved human bone marrow stroma is fully functional in vitro.

Human-marrow long-term culture (LTC) enables maintenance of both stromal and haemopoietic elements of normal bone marrow (NBM) in vitro for 4-6 months. Stroma-based cultures are critical for quantitation of long-term culture initiating cells (LTC-IC), the most primitive human haemopoietic cells measurable in vitro. Supply of NBM can be sporadic, and up to 3-4 weeks in culture is required for stromal maturity. Stroma availability for experimental purposes can therefore be limited. Efforts to produce transformed human and transfected murine stromal cell lines comparable to NBM stroma have had some success. As an alternative, we investigated cryopreserved NBM and cryopreserved performed stroma. Function of cryopreserved and control fresh NBM stroma was similar when evaluated for up to 12 weeks in LTC. We have also demonstrated that stroma derived from cryopreserved NBM or performed cryopreserved NBM stroma can sustain third-party haemopoiesis as efficiently as fresh NBM stroma in LTC. Batched cryopreserved stroma is a convenient, rapidly available, source of functional stroma which avoids the logistic difficulties and lack of standardization associated with stroma from fresh NBM. This important advance will enhance the use of stroma-based LTC in studies of human haemopoiesis.

Bone Marrow↗
PubMed2002

Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling.

PURPOSE: Generation of a reactive stroma environment occurs in many human cancers and is likely to promote tumorigenesis. However, reactive stroma in human prostate cancer has not been defined. We examined stromal cell phenotype and expression of extracellular matrix components in an effort to define the reactive stroma environment and to determine its ontogeny during prostate cancer progression. EXPERIMENTAL DESIGN: Normal prostate, prostatic intraepithelial neoplasia (PIN), and prostate cancer were examined by immunohistochemistry. Tissue samples included radical prostatectomy specimens, frozen biopsy specimens, and a prostate cancer tissue microarray. A human prostate stromal cell line was used to determine whether transforming growth factor beta1 (TGF-beta1) regulates reactive stroma. RESULTS: Compared with normal prostate tissue, reactive stroma in Gleason 3 prostate cancer showed increased vimentin staining and decreased calponin staining (P < 0.001). Double-label immunohistochemistry revealed that reactive stromal cells were vimentin and smooth muscle alpha-actin positive, indicating the myofibroblast phenotype. In addition, reactive stroma cells exhibited elevated collagen I synthesis and expression of tenascin and fibroblast activation protein. Increased vimentin expression and collagen I synthesis were first observed in activated periacinar fibroblasts adjacent to PIN. Similar to previous observations in prostate cancer, TGF-beta1-staining intensity was elevated in PIN. In vitro, TGF-beta1 stimulated human prostatic fibroblasts to switch to the myofibroblast phenotype and to express tenascin. CONCLUSIONS: The stromal microenvironment in human prostate cancer is altered compared with normal stroma and exhibits features of a wound repair stroma. Reactive stroma is composed of myofibroblasts and fibroblasts stimulated to express extracellular matrix components. Reactive stroma appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular stroma. These studies and others suggest that TGF-beta1 is a candidate regulator of reactive stroma during prostate cancer progression.

Adenocarcinoma↗
PubMed1994

Identification of Philadelphia-negative granulocyte-macrophage colony-forming units generated by stroma-adherent cells from chronic myelogenous leukemia patients.

Chronic myelogenous leukemia (CML) is a clonal disorder of the hematopoietic stem cell characterized by the coexistence of Philadelphia-negative (Ph-) with Ph+ progenitors. CML progenitor cells have been shown to be defective in adherence to marrow stroma. The present study investigated at the cytogenetic level marrow-derived CML clonogenic cells generated from the stroma-adherent cell fraction. On direct cytogenetic analysis, the overall mean (+/- SEM) percentage of Ph- metaphases was 3% +/- 1%. Mononuclear marrow cells from CML patients (n = 18) were incubated with mafosfamide (100 micrograms/mL) or control medium, seeded onto marrow stromal layers and allowed to adhere (2 hours, 37 degrees C). After a short-term (3-day) liquid culture, the cells were harvested, incorporated in methyl-cellulose, and individual colonies were analyzed by single colony karyotyping. The mean (+/- SEM) percentage of Ph- colonies generated from the stroma-adherent fraction was 35% +/- 6%. As compared with marrow colony-forming unit granulocyte-macrophage plated before any manipulation, the mean (+/- SEM) percentage of Ph- clones was significantly increased by stroma adherence (35% +/- 6% v 15% +/- 4%, P < or = .005) and mafosfamide (100 micrograms/mL) incubation of marrow cells before stroma adherence (58% +/- 9% v 35% +/- 6%, P < or = .005). An additive effect was observed by combining mafosfamide treatment and stroma adherence. Single-colony transfer experiments showed that 50% +/- 4% stroma-adherent and 70% +/- 4% stroma-adherent mafosfamide-treated progenitors gave rise to secondary colonies. To further characterize the stroma-adherent fraction, experiments were performed in which CD34+ marrow cells were used. The mean (+/- SEM) output of progenitors generated by 10,000 CD34+, stroma-adherent cells was 888 +/- 188 and 570 +/- 258 for untreated and mafosfamide-treated cells, respectively. Individual colonies were analyzed by single-colony karyotyping and fluorescent in situ hybridization using a biotinylated cosmid DNA probe that hybridize to abl oncogene. The CD34+, stroma-adherent fraction contained 38% +/- 14% (untreated) and 56% +/- 18% (mafosfamide-treated) (P < or = .025) Ph- progenitors. In conclusion, the present data show the possibility to select Ph- clones that (1) have a maintained capability of stroma adherence, (2) are mafosfamide resistant, (3) are derived from the CD34+ fraction, and (4) have high-replating potential.

Adult↗
PubMed1993

Soluble factor(s) produced by human bone marrow stroma increase cytokine-induced proliferation and maturation of primitive hematopoietic progenitors while preventing their terminal differentiation.

We have recently shown that conservation and differentiation of primitive human hematopoietic progenitors in in vitro long-term bone marrow cultures (LTBMC) occurs to a greater extent when hematopoietic cells are grown separated from the stromal layer than when grown in direct contact with the stroma. This finding suggests that hematopoiesis may depend mainly on soluble factors produced by the stroma. To define these soluble factors, we examine here whether a combination of defined early-acting cytokines can replace soluble stroma-derived biologic activities that induce conservation and differentiation of primitive progenitors. Normal human Lineage-/CD34+/HLA-DR- cells (DR-) were cultured either in the absence of a stromal layer ("stroma-free") or in a culture system in which DR- cells were separated from the stromal layer by a microporous membrane ("stroma-noncontact"). Both culture systems were supplemented three times per week with or without cytokines. These studies show that culture of DR- cells for 5 weeks in a "stroma-free" culture supplemented with a combination of four early acting cytokines (Interleukin-3 [IL-3], stem cell factor [SCF], leukemia-inhibitory factor [LIF], and granulocyte colony-stimulating factor [G-CSF]) results in a similar cell expansion as when DR- cells are cultured in "stroma-noncontact" cultures supplemented with the same cytokines. However, generation of committed progenitors and conservation of the more primitive long-term bone marrow culture initiating cells (LTBMC-IC) was far superior in "stroma-noncontact" cultures supplemented with or without IL-3 than in "stroma-free" cultures supplemented with IL-3 alone or a combination of IL-3, LIF, G-CSF, and SCF. These studies indicate that human BM stroma produces soluble factors that can either alone or in synergy with defined cytokines (1) conserve primitive LTBMC-IC, (2) induce early differentiation of a fraction of the primitive progenitors, and (3) prevent their terminal differentiation. We show here that these stroma-derived factors are not likely to be the known early acting cytokines IL-3, SCF, LIF, or G-CSF. Characterization of the stroma-derived factor(s) may have important implications for clinically relevant studies, such as in vitro stem cell expansion in cancer treatment and gene therapy.

Bone Marrow↗