Статті в журналах: "Colon fibroblasts"

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Laudadio, Ilaria, Alex Bastianelli, Valerio Fulci, Claudia Carissimi, Eleonora Colantoni, Francesca Palone, Roberta Vitali та ін. "ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis". International Journal of Molecular Sciences 23, № 18 (6 вересня 2022): 10261. http://dx.doi.org/10.3390/ijms231810261.

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Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.

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Bruckner, R. S., M. C. Barnhoorn, H. Mei, S. M. Kiełbasa, T. J. Harrijvan, S. K. Hakuno, J. J. van der Reijden, A. E. van der Meulen-de Jong, and L. J. A. C. Hawinkels. "DOP85 The role of fibroblasts in the pathogenesis of Crohn’s disease-associated fistulas and in mesenchymal stem cell therapy." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S125. http://dx.doi.org/10.1093/ecco-jcc/jjz203.124.

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Abstract Background Perianal fistulas are a severe and frequent complication in Crohn’s disease (CD) patients, significantly affecting their quality of life. High recurrence rates, incomplete fistula healing and non-responding patients make the treatment challenging. Despite some novel insights, current knowledge about the pathogenesis of fistula formation is still limited. Fibroblasts are abundantly present in CD fistulas and were recently reported to regulate Th1 cell activity in inflammatory bowel disease (IBD) (Beswick EJ et al. 2018). We hypothesised that fibroblasts act as the key drivers of fistula pathogenesis by regulating inflammatory cell recruitment. Methods Fibroblasts were isolated from curettage material of perianal CD fistulas, non-CD-associated fistulas, and the normal colon (obtained at surgery for colorectal cancer at least 10 cm away from the primary tumour). For all experiments, fibroblast populations were identified by qPCR and flow cytometry analysis first. Then gene expression profiling via mRNA sequencing of cultured fistula- and colon-derived fibroblasts was performed. The characterisation was complemented by flow cytometry analysis. Furthermore, the interaction of fistula-derived fibroblasts with regulatory T cells (Tregs) was studied in co-culture experiments. Results mRNA sequencing analysis revealed no significant differences in gene expression between perianal CD fistulas and non-CD-associated fistulas. However, comparing fistula-derived samples to fibroblasts derived from the normal colon, we found over 6000 significantly differentially expressed genes. Among the 20 most significant differentially expressed genes between CD fistulas and colon fibroblasts were genes related to epithelial-mesenchymal transition, cell migration or the NF-κB signalling pathway. Furthermore, co-culture experiments with CD fistula-derived fibroblasts, revealed increased proliferation rates of CD25+FoxP3+ Treg cells. In addition, more CD4+ T cells differentiated into Treg cells after exposure to CD fistula fibroblasts. Conclusion Our data indicate a pathogenic role of fibroblasts located in the fistula tract. Their gene expression profile markedly differed from fibroblasts derived from the normal part of the colon. Based on our data, there is no difference between CD-associated and non-CD-associated fistula fibroblasts. CD fistula-derived fibroblasts seem to increase both the proliferation of Treg cells, and the differentiation of CD4+ T cells into Treg cells, indicating an important immunoregulatory role of fibroblasts. Ongoing experiments should reveal which cytokines and chemokines are involved in this process.

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Jasso, Guadalupe J., Alok Jaiswal, Mukund Varma, Tyler Laszewski, Angelo Grauel, Abdifatah Omar, Nilsa Silva, et al. "Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing." PLOS Biology 20, no. 1 (January 27, 2022): e3001532. http://dx.doi.org/10.1371/journal.pbio.3001532.

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Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11–producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.

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Fuhr, Abreu, Carbone, El-Athman, Bianchi, Laukkanen, Mazzoccoli, and Relógio. "The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes." Cancers 11, no. 7 (July 15, 2019): 988. http://dx.doi.org/10.3390/cancers11070988.

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Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics.

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Herrera, Mercedes, Artur Mezheyeuski, Lisa Villabona, Sara Corvigno, Carina Strell, Christian Klein, Gabriele Hölzlwimmer, et al. "Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer." Cancers 12, no. 11 (November 3, 2020): 3238. http://dx.doi.org/10.3390/cancers12113238.

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Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

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Heichler, Christina, Kristina Scheibe, Anabel Schmied, Carol I. Geppert, Benjamin Schmid, Stefan Wirtz, Oana-Maria Thoma, et al. "STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis." Gut 69, no. 7 (November 4, 2019): 1269–82. http://dx.doi.org/10.1136/gutjnl-2019-319200.

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ObjectiveCancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.DesignWe quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI–) on STAT3 activation (IL-6 vs IL-11).ResultsThe analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.ConclusionAltogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.

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Knowles, Jonathan P., Xu Shi-Wen, Samer-ul Haque, Ashish Bhalla, Michael R. Dashwood, Shiyu Yang, Irving Taylor, Marc C. Winslet, David J. Abraham, and Marilena Loizidou. "Endothelin-1 stimulates colon cancer adjacent fibroblasts." International Journal of Cancer 130, no. 6 (June 9, 2011): 1264–72. http://dx.doi.org/10.1002/ijc.26090.

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Brügger, Michael David, Tomas Valenta, Hassan Fazilaty, George Hausmann, and Konrad Basler. "Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis." PLOS Biology 18, no. 12 (December 11, 2020): e3001032. http://dx.doi.org/10.1371/journal.pbio.3001032.

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Despite recent progress in recognizing the importance of mesenchymal cells for the homeostasis of the intestinal system, the current picture of how these cells communicate with the associated epithelial layer remains unclear. To describe the relevant cell populations in an unbiased manner, we carried out a single-cell transcriptome analysis of the adult murine colon, producing a high-quality atlas of matched colonic epithelium and mesenchyme. We identify two crypt-associated colonic fibroblast populations that are demarcated by different strengths of platelet-derived growth factor receptor A (Pdgfra) expression. Crypt-bottom fibroblasts (CBFs), close to the intestinal stem cells, express low levels of Pdgfra and secrete canonical Wnt ligands, Wnt potentiators, and bone morphogenetic protein (Bmp) inhibitors. Crypt-top fibroblasts (CTFs) exhibit high Pdgfra levels and secrete noncanonical Wnts and Bmp ligands. While the Pdgfralow cells maintain intestinal stem cell proliferation, the Pdgfrahigh cells induce differentiation of the epithelial cells. Our findings enhance our understanding of the crosstalk between various colonic epithelial cells and their associated mesenchymal signaling hubs along the crypt axis—placing differential Pdgfra expression levels in the spotlight of intestinal fibroblast identity.

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Kikuchi, Yoshinao, Takeshi G. Kashima, Takashi Nishiyama, Kazuhiro Shimazu, Yasuyuki Morishita, Masashi Shimazaki, Isao Kii, et al. "Periostin Is Expressed in Pericryptal Fibroblasts and Cancer-associated Fibroblasts in the Colon." Journal of Histochemistry & Cytochemistry 56, no. 8 (April 14, 2008): 753–64. http://dx.doi.org/10.1369/jhc.2008.951061.

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Agrawal, Khushboo, Viswanath Das, Natálie Táborská, Ján Gurský, Petr Džubák, and Marián Hajdúch. "Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs." Stem Cells International 2018 (August 12, 2018): 1–11. http://dx.doi.org/10.1155/2018/6013728.

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The advanced-stage colon cancer spreads from primary tumor site to distant organs where the colon-unassociated stromal population provides a favorable niche for the growth of tumor cells. The heterocellular interactions between colon cancer cells and colon-unassociated fibroblasts at distant metastatic sites are important, yet these cell-cell interactions for therapeutic strategies for metastatic colon cancer remain underestimated. Recent studies have shown the therapeutic potential of DNA-demethylating epi-drugs 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine (DAC) for the treatment of solid tumors. While the effects of these epi-drugs alone or in combination with other anticancer therapies are well described, the influence of stromal cells and their secretome on cancer cell response to these agents remain elusive. In this study, we determined the effect of normal and senescent colon-unassociated fibroblasts and their conditioned medium on colorectal cancer (CRC) cell response to AZA and DAC using a cell-based DNA demethylation reporter system. Our data show that fibroblasts accelerate cell proliferation and differentially regulate the expression of DNA methylation-regulating enzymes, enhancing DAC-induced demethylation in CRC cells. In contrast, the conditioned medium from senescent fibroblasts that upregulated NF-κB activity altered deoxycytidine kinase levels in drug-untreated CRC cells and abrogated DAC effect on degradation of DNA methyltransferase 1. Similar to 2D cultures, senescent fibroblasts increased DNA demethylation of CRC cells in coculture spheroids, in addition to increasing the stemness of CRC cells. This study presents the first evidence of the effect of normal and senescent stromal cells and their conditioned medium on DNA demethylation by DAC. The data show an increased activity of DAC in high stromal cell cocultures and suggest the potential of the tumor-stroma ratio in predicting the outcome of DNA-demethylating epigenetic cancer therapy.

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Drev, Daniel, Felix Harpain, Andrea Beer, Anton Stift, Elisabeth S. Gruber, Martin Klimpfinger, Sabine Thalhammer, et al. "Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells." Cancers 11, no. 10 (September 24, 2019): 1421. http://dx.doi.org/10.3390/cancers11101421.

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Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC expression in patients suffering from stage II and III CRC using a publicly available mRNA data set and immunohistochemistry of tissue microarray sections. Moreover, in vitro co-culture models using CRC cell lines together with colon-associated fibroblasts were established to determine the effect of fibroblast-derived SPARC on cancer cells. In 466 patient samples, high SPARC mRNA was associated with a shorter disease-free survival. In 99 patients of the tissue microarray cohort, high stromal SPARC in the primary tumor was an independent predictor of shorter survival in patients with relapse (27 cases; HR = 4574, p = 0.004). In CRC cell lines, SPARC suppressed phosphorylation of focal adhesion kinase and stimulated cell migration. Colon-associated fibroblasts increased migration velocity by 30% and doubled track-length in SPARC-dependent manner. In a 3D co-culture system, fibroblast-derived SPARC enhanced tumor cell invasion. Taken together, stromal SPARC had a pro-metastatic impact in vitro and was a characteristic of aggressive tumors with poor prognosis in CRC patients.

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Zidar, D. A. "Fibroblasts in Colon Cancer: Turned Traitor by Chemotherapy." Science Translational Medicine 6, no. 217 (January 1, 2014): 217ec3. http://dx.doi.org/10.1126/scitranslmed.3008240.

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Sameni, Mansoureh, Julie Dosescu, Kamiar Moin, and Bonnie F. Sloane. "Functional Imaging of Proteolysis: Stromal and Inflammatory Cells Increase Tumor Proteolysis." Molecular Imaging 2, no. 3 (July 1, 2003): 153535002003031. http://dx.doi.org/10.1162/15353500200303136.

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The underlying basement membrane is degraded during progression of breast and colon carcinoma. Thus, we imaged degradation of a quenched fluorescent derivative of basement membrane type IV collagen (DQ-collagen IV) by living human breast and colon tumor spheroids. Proteolysis of DQ-collagen IV by HCT 116 and HKh-2 human colon tumor spheroids was both intracellular and pericellular. In contrast, proteolysis of DQ-collagen IV by BT20 human breast tumor spheroids was pericellular. As stromal elements can contribute to proteolytic activities associated with tumors, we also examined degradation of DQ-collagen IV by human monocytes/macrophages and colon and breast fibroblasts. Fibroblasts themselves exhibited a modest amount of pericellular degradation. Degradation was increased 4–17-fold in cocultures of fibroblasts and tumor cells as compared to either cell type alone. Inhibitors of matrix metalloproteinases, plasmin, and the cysteine protease, cathepsin B, all reduced degradation in the cocultures. Monocytes did not degrade DQ-collagen IV; however, macrophages degraded DQ-collagen IV intracellularly. In coculture of tumor cells, fibroblasts, and macrophages, degradation of DQ-collagen IV was further increased. Imaging of living tumor and stromal cells has, thus, allowed us to establish that tumor proteolysis occurs pericellularly and intracellularly and that tumor, stromal, and inflammatory cells all contribute to degradative processes.

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Martens, M. F., C. M. Huyben, and T. Hendriks. "Collagen synthesis in fibroblasts from human colon: regulatory aspects and differences with skin fibroblasts." Gut 33, no. 12 (December 1, 1992): 1664–70. http://dx.doi.org/10.1136/gut.33.12.1664.

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Zhu, Yingting, Ping Hua, Shazia Rafiq, Eric J. Waffner, Michael E. Duffey, and Peter Lance. "Ca2+- and PKC-dependent stimulation of PGE2 synthesis by deoxycholic acid in human colonic fibroblasts." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 3 (September 1, 2002): G503—G510. http://dx.doi.org/10.1152/ajpgi.00525.2001.

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We investigated prostanoid biogenesis by human colonic fibroblasts (CCD-18Co cells and nine primary fibroblast cultures) exposed to a primary (cholic, CA) or a secondary (deoxycholic, DCA) bile acid. Basal PGE2 levels in CCD-18Co cultures and fibroblast strains initiated from normal and adenocarcinomatous colon, respectively, were 1.7 ± 0.3, 4.0 ± 2.0, and 15.0 ± 4.8 ng/mg protein. Peak levels 24 h after exposure to DCA (300 μM) rose, respectively, seven-, six- and sevenfold, but CA elicited no such responses. Increases in PGE2 synthesis were preceded by sequential increases in PGH synthase-2 mRNA and protein expression and were fully prevented by a nonselective (indomethacin) or a selective (celecoxib) nonsteroidal anti-inflammatory drug. DCA, but not CA, caused abrupt, transient increases in fibroblast intracellular Ca2+ concentration ([Ca2+]i) ∼1 min after exposure. Increased [Ca2+]i was required for DCA-mediated induction of PGE2 synthesis, and protein kinase C was a further essential component of this signaling pathway. Colonic fibroblasts may be a major target for prostanoid biogenesis induced by fecal bile acids and, potentially, other noxious actions of these agents.

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Chesnokova, Vera, Svetlana Zonis, Cuiqi Zhou, Maria Victoria Recouvreux, Anat Ben-Shlomo, Takako Araki, Robert Barrett, et al. "Growth hormone is permissive for neoplastic colon growth." Proceedings of the National Academy of Sciences 113, no. 23 (May 25, 2016): E3250—E3259. http://dx.doi.org/10.1073/pnas.1600561113.

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Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)−/− mice exhibited induced colon p53 levels, and cross-breeding them with Apcmin+/− mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear β-catenin accumulation, and increased epithelial–mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the “field change” milieu permissive for neoplastic colon growth.

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Dias Carvalho, Patrícia, Susana Mendonça, Flávia Martins, Maria José Oliveira, and Sérgia Velho. "Modulation of Fibroblast Phenotype by Colorectal Cancer Cell-Secreted Factors Is Mostly Independent of Oncogenic KRAS." Cells 11, no. 16 (August 11, 2022): 2490. http://dx.doi.org/10.3390/cells11162490.

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KRAS mutations have been shown to extend their oncogenic effects beyond the cancer cell, influencing the tumor microenvironment. Herein, we studied the impact of mutant KRAS on the modulation of the pro-tumorigenic properties of cancer-associated fibroblasts (CAFs), including α-SMA expression, TGFβ1 and HGF production, extracellular matrix components and metalloproteinases expression as well as collagen contraction and migration capacities. To do so, CCD-18Co normal-like colon fibroblasts were challenged with conditioned media from control and KRAS silenced colorectal cancer (CRC) cells. Our results showed that the mutant KRAS CRC cell-secreted factors were capable of turning normal-like fibroblasts into CAF-like by modulating the α-SMA expression, TGFβ1 and HGF production and migration capacity. Oncogenic KRAS played a secondary role as its silencing did not completely impair the capacity of CRC cells to modulate most of the fibroblast properties analyzed. In summary, our work suggests that mutant KRAS does not play a major role in controlling the CRC cell-secreted factors that modulate the behavior of fibroblasts. The fact that CRC cells retain the capacity to modulate the pro-tumorigenic features of fibroblasts independently of KRAS silencing is likely to negatively impact their response to KRAS inhibitors, thus standing as a putative mechanism of resistance to KRAS inhibition with potential therapeutical relevance.

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Desnoyers, Luc, David Arnott, and Diane Pennica. "WISP-1 Binds to Decorin and Biglycan." Journal of Biological Chemistry 276, no. 50 (October 11, 2001): 47599–607. http://dx.doi.org/10.1074/jbc.m108339200.

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Wnt-1-induced secreted protein 1 (WISP-1) is a member of the CCN (connective tissue growth factor,Cyr61,NOV) family of growth factors. Structural and experimental evidence suggests that CCN family member activities are modulated by their interaction with sulfated glycoconjugates. To elucidate the mechanism of action for WISP-1, we characterized the specificity of its tissue and cellular interaction and identified binding factors. WISP-1 binding was restricted to the stroma of colon tumors and to cells with a fibroblastic phenotype. By using a solid phase assay, we showed that human skin fibroblast conditioned media contained WISP-1 binding factors. Competitive inhibition with different glycosaminoglycans and treatment with glycosaminoglycan lyases and proteases demonstrated that binding to the conditioned media was mediated by dermatan sulfate proteoglycans. Mass spectrometric analysis identified the isolated binding factors as decorin and biglycan. Decorin and biglycan interacted directly with WISP-1 and inhibited its binding to components in the conditioned media. Similarly, WISP-1 interaction with human skin fibroblasts was inhibited by dermatan sulfate, decorin, and biglycan or by treatment of the cell surface with dermatan sulfate-specific lyases. Together these results demonstrate that decorin and biglycan are WISP-1 binding factors that can mediate and modulate its interaction with the surface of fibroblasts. We propose that this specific interaction plays a role in the regulation of WISP-1 function.

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Mahadevan, Swarna, Kenelm Kwong, Mingjie Lu, Elizabeth Kelly, Belal Chami, Yevgeniy Romin, Sho Fujisawa, Katia Manova, Malcolm A. S. Moore, and Hans Zoellner. "A Novel Cartesian Plot Analysis for Fixed Monolayers That Relates Cell Phenotype to Transfer of Contents between Fibroblasts and Cancer Cells by Cell-Projection Pumping." International Journal of Molecular Sciences 23, no. 14 (July 19, 2022): 7949. http://dx.doi.org/10.3390/ijms23147949.

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We recently described cell-projection pumping as a mechanism transferring cytoplasm between cells. The uptake of fibroblast cytoplasm by co-cultured SAOS-2 osteosarcoma cells changes SAOS-2 morphology and increases cell migration and proliferation, as seen by single-cell tracking and in FACS separated SAOS-2 from co-cultures. Morphological changes in SAOS-2 seen by single cell tracking are consistent with previous observations in fixed monolayers of SAOS-2 co-cultures. Notably, earlier studies with fixed co-cultures were limited by the absence of a quantitative method for identifying sub-populations of co-cultured cells, or for quantitating transfer relative to control populations of SAOS-2 or fibroblasts cultured alone. We now overcome that limitation by a novel Cartesian plot analysis that identifies individual co-cultured cells as belonging to one of five distinct cell populations, and also gives numerical measure of similarity to control cell populations. We verified the utility of the method by first confirming the previously established relationship between SAOS-2 morphology and uptake of fibroblast contents, and also demonstrated similar effects in other cancer cell lines including from melanomas, and cancers of the ovary and colon. The method was extended to examine global DNA methylation, and while there was no clear effect on SAOS-2 DNA methylation, co-cultured fibroblasts had greatly reduced DNA methylation, similar to cancer associated fibroblasts.

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Onfroy-Roy, Lauriane, Dimitri Hamel, Laurent Malaquin, and Audrey Ferrand. "Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?" Cancers 13, no. 8 (April 7, 2021): 1749. http://dx.doi.org/10.3390/cancers13081749.

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Colorectal cancer (CRC) is the third most common cause of cancer-related death. Significant improvements in CRC treatment have been made for the last 20 years, on one hand thanks to a better detection, allowing surgical resection of the incriminated area, and on the other hand, thanks to a better knowledge of CRC’s development allowing the improvement of drug strategies. Despite this crucial progress, CRC remains a public health issue. The current model for CRC initiation and progression is based on accumulation of sequential known genetic mutations in the colon epithelial cells’ genome leading to a loss of control over proliferation and survival. However, increasing evidence reveals that CRC initiation is more complex. Indeed, chronic inflammatory contexts, such as inflammatory bowel diseases, have been shown to increase the risk for CRC development in mice and humans. In this manuscript, we review whether colon fibroblasts can go from the main regulators of the ISC homeostasis, regulating not only the renewal process but also the epithelial cells’ differentiation occurring along the colon crypt, to the main player in the initiation of the colorectal cancer process due to chronic inflammation.

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Hoorde, Leen van, Katleen Braet, and Marc Mareel. "The N-Cadherin/Catenin Complex in Colon Fibroblasts and Myofibroblasts." Cell Adhesion and Communication 7, no. 2 (January 1999): 139–50. http://dx.doi.org/10.3109/15419069909034397.

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Herrera, Alberto, Mercedes Herrera, Lorena Alba-Castellón, Javier Silva, Vanesa García, Jordina Loubat-Casanovas, Ana Álvarez-Cienfuegos, et al. "Protumorigenic effects of Snail-expression fibroblasts on colon cancer cells." International Journal of Cancer 134, no. 12 (November 29, 2013): 2984–90. http://dx.doi.org/10.1002/ijc.28613.

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Dias, Manoela Maciel dos Santos, Hércia Stampini Duarte Martino, Giuliana Noratto, Andrea Roque-Andrade, Paulo César Stringheta, Stephen Talcott, Afonso Mota Ramos, and Susanne U. Mertens-Talcott. "Anti-inflammatory activity of polyphenolics from açai (Euterpe oleracea Martius) in intestinal myofibroblasts CCD-18Co cells." Food & Function 6, no. 10 (2015): 3249–56. http://dx.doi.org/10.1039/c5fo00278h.

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Owusu, Benjamin Y., Mudit Vaid, Pawan Kaler, and Lidija Klampfer. "Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer." Biomarkers in Cancer 7s1 (January 2015): BIC.S25247. http://dx.doi.org/10.4137/bic.s25247.

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Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment. Recent advances in the understanding of the involvement of the tumor microenvironment in tumor progression and therapeutic response are optimizing the application of prognostic and predictive factors in colon cancer. Moreover, new targets in the tumor microenvironment that are amenable to therapeutic intervention have been identified. Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs. In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

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Ozden, Ozkan, та Seong-Hoon Park. "SIRT2 mediated downregulation of FOXM1 in response to TGFβ through the RAF-MEK-ERK signaling pathway in colon cancer". Archives of Biological Sciences 73, № 2 (2021): 257–64. http://dx.doi.org/10.2298/abs210227020o.

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The transcription factor forkhead box M1 (FOXM1) is frequently upregulated in many solid tumors, including those in the colon. As a master regulator, the sirtuin (SIRT) protein family is comprised of seven nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases/adenosine diphosphate (ADP) ribosyl transferases whose activities are associated with aging and cancer. In this study, we determined whether a cytoplasmic member of SIRTs, SIRT2, influences the expression of oncogenic FOXM1 in colon cancer in vitro. The association of SIRT2 and FOXM1 were analyzed using SIRT2 knockout mouse embryonic fibroblasts and SIRT2 knocked-down and overexpressing HCT116 colon cancer cell lines. Cell lines were treated with 10 ng/mL transforming growth factor-beta (TGFR) for 24 h. SIRT2 could downregulate FOXM1 through the TGF? mitogen-activated protein kinase (RAF-MEK-ERK) signaling pathway in genetically altered mouse embryonic fibroblasts and colon cancer cell lines. The indirect association between SIRT2 and FOXM1 through TGF? may be important because activators or inhibitors of SIRT2 could provide a potential approach to downregulate FOXM1 in gastrointestinal cancers.

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Hsia, Lin-ting, Neil Ashley, Djamila Ouaret, Lai Mun Wang, Jennifer Wilding, and Walter F. Bodmer. "Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): E2162—E2171. http://dx.doi.org/10.1073/pnas.1603534113.

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Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumor progression. Myofibroblasts previously have been distinguished from normal fibroblasts mostly by the expression of α smooth muscle actin (αSMA). We now have identified AOC3 (amine oxidase, copper containing 3), a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast-reacting mAb PR2D3. The normal and tumor tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by nonenzymatic procedures. Whole-genome microarray mRNA-expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly differentially expressed in these two cell types: NKX2-3 and LRRC17 in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. TGFβ substantially down-regulated AOC3 expression in myofibroblasts but in skin fibroblasts it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and increased expression of the fibroblast-associated gene SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3, and other markers, are a distinctly different cell type from TGFβ-activated fibroblasts.

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Adegboyega, Patrick A., Randy C. Mifflin, John F. DiMari, Jamal I. Saada, and Don W. Powell. "Immunohistochemical Study of Myofibroblasts in Normal Colonic Mucosa, Hyperplastic Polyps, and Adenomatous Colorectal Polyps." Archives of Pathology & Laboratory Medicine 126, no. 7 (July 1, 2002): 829–36. http://dx.doi.org/10.5858/2002-126-0829-isomin.

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Abstract Context.—Myofibroblasts are distinct cells with characteristics of both smooth muscle cells and fibroblasts. Through their ability to secrete cytokines, chemokines, prostaglandins, growth factors, and matrix components, they are thought to play critical roles in inflammation, growth, repair, and neoplasia. Objective.—The goal of this study was to identify the distinct cell populations of the lamina propria of normal colon and colorectal polyps. Design.—We studied the expression of α-smooth muscle actin (αSMA), smooth muscle myosin (SMM), desmin, vimentin, and c-kit by intestinal mesenchymal (stromal) cells in the normal colonic mucosa (n = 5), as well as in hyperplastic polyps (n = 5), sporadic colorectal adenomas (n = 47), and adenomas from patients with familial polyposis (n = 36). Results.—In the normal colonic mucosa, the pericryptal stromal cells were αSMA+, SMM+, desmin−, and vimentin+, defining them as myofibroblasts. In contrast, cells of the muscularis mucosae were αSMA+, SMM+, desmin+, and vimentin−, defining them as smooth muscle cells. α-Smooth muscle actin also highlighted direct connections between the muscularis mucosae and the pericryptal myofibroblasts, and vimentin immunostaining showed a network of connections between the αSMA+ pericryptal myofibroblasts and the αSMA− fibroblasts in the interstitium. In all hyperplastic polyps and adenomatous polyps, the interstitial stromal cells (fibroblasts) now also express αSMA and form a syncytium of αSMA+ networklike connections throughout the lamina propria. Stromal cells of sporadic adenomas demonstrated the same immunohistochemical staining characteristics displayed by adenomas from patients with familial polyposis and by hyperplastic polyps. Conclusions.—These findings indicate that in normal colon, αSMA− fibroblasts are the predominant cell type in the lamina propria. However, the pericryptal (subepithelial) stromal cells are a distinct cell type (αSMA+ myofibroblast) that is immunophenotypically different from muscularis mucosae smooth muscle cells and are connected to the interstitial, nonpericryptal fibroblasts with which they exist as a network throughout the lamina propria of the normal colon. Furthermore, in both hyperplastic and neoplastic polyps, there are changes in nonpericryptal fibroblasts from vimentin+, αSMA−, and SMM− to vimentin+, αSMA+, and SMM+; thus, the interstitial fibroblasts are replaced by myofibroblasts. The factors that cause these changes and the origin of the myofibroblasts need to be determined to clarify the biology of colorectal tumorigenesis.

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Xuefeng, Xuefeng, Ming-Xing Hou, Zhi-Wen Yang, Agudamu Agudamu, Feng Wang, Xiu-Lan Su, Xian Li, et al. "Epithelial–mesenchymal transition and metastasis of colon cancer cells induced by the FAK pathway in cancer-associated fibroblasts." Journal of International Medical Research 48, no. 6 (June 2020): 030006052093124. http://dx.doi.org/10.1177/0300060520931242.

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Objective The role and mechanism of tetrathiomolybdate (TM) in cancer-associated fibroblasts (CAFs) in colon cancer using three-dimensional (3D) culture were investigated, and the associations between the focal adhesion kinase (FAK) pathway and epithelial–mesenchymal transition (EMT) in CAFs were explored. Methods A 3D co-culture model of colon cancer LOVO cells with CAFs and normal fibroblasts (NFs) was established using Matrigel as a scaffold material. The differential expression of LOXL2 (lysyl oxidase-like 2) in the supernatant of CAFs and NFs was determined using ELISA, and expression levels of EMT-related proteins and FAK signaling pathway-related proteins were determined using western blot. Results LOXL2 levels secreted by CAFs were higher compared with that secreted by NFs. In the CAF + LOVO group, compared with the LOVO group, E-cadherin expression decreased significantly, while N-cadherin and F-PAK expression increased significantly. TM results were opposite compared with the above results. Conclusions CAFs stimulate EMT in human colon cancer LOVO cells by secreting LOXL2 to activate the FAK signaling pathway, thereby promoting tumor metastasis. TM inhibited the occurrence of EMT in the CAF-induced colon cancer LOVO cell line, thereby reducing the invasion and metastasis of colon cancer cells.

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Zhou, Z., L. G. Plug, E. S. M. de Jonge-Muller, L. M. van de Beek, L. Brands, A. E. van der Meulen-de Jong, L. J. A. C. Hawinkels, and M. C. Barnhoorn. "P036 Identification and functional analysis of stromal subsets in experimental IBD mouse models." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i154—i155. http://dx.doi.org/10.1093/ecco-jcc/jjab232.165.

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Abstract Background Single cell RNA sequencing data from the inflamed colon of inflammatory bowel disease (IBD) patients revealed the presence of different stromal cell/fibroblast subsets and showed their importance in IBD pathology. Up to now, it is unknown if and how the stroma cells affect disease progression. In this study we compared the stromal cell subsets in three IBD mouse models and explored the interaction between these stromal subsets and epithelial cells. Methods Stromal cell subset markers, including CD55, C-X-C motif chemokine 12 (CXCL12), podoplanin (PDPN), CD90 and CD73, were analyzed in the inflamed murine colon by flow cytometry in interleukin (IL)-10 knockout (KO) mice, dextran sulfate sodium(DSS)-induced colitis and the T cell transfer model. In order to explore the changes in stromal subsets upon colitis induction in vitro, short hairpin RNAs were used to silence target gene expression of these cellular markers in murine fibroblasts. Fibroblast proliferation and migration was studied in addition to the effects on immune cell trafficking and tissue regeneration. Results In all three colitis models, an increase in the total amount of stromal cells was observed. The percentages of PDPN+ and CD73+ stromal cells significantly increased during colitis in the IL-10 KO mice, while the percentage of CD55+, CD90+ and CXCL12+ stromal cells decreased. For the T cell transfer model, the abundance of CD73+, CD90+ and CD55+ stromal cells was enriched, while the percentage of CXCL12+ stromal cells was reduced. Interestingly, in contrast to the two other, in the DSS-mice the percentage of CXCL12+ stromal cells was significantly increased. In vitro experiments showed the importance of CD55 and CXCL12 for fibroblast proliferation and CD55 for their migration. Furthermore, the fibroblast supernatant obtained after the knockdown of CXCL12 decreased epithelial cell wound healing. On the contrary, knock-down of CD90 in the fibroblasts improved epithelial migration. Current experiments explore the immune regulatory properties of the fibroblast subsets. Conclusion The composition of stromal cell subsets is significantly changed in experimental colitis and differs between three established colitis mouse models. Therefore they may possibly reflect different human IBD subtypes observed in the clinic. Finally the defined subsets influence fibroblast behavior and epithelial regeneration.

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Keller, Florian, Roman Bruch, Richard Schneider, Julia Meier-Hubberten, Mathias Hafner, and Rüdiger Rudolf. "A Scaffold-Free 3-D Co-Culture Mimics the Major Features of the Reverse Warburg Effect In Vitro." Cells 9, no. 8 (August 13, 2020): 1900. http://dx.doi.org/10.3390/cells9081900.

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Most tumors consume large amounts of glucose. Concepts to explain the mechanisms that mediate the achievement of this metabolic need have proposed a switch of the tumor mass to aerobic glycolysis. Depending on whether primarily tumor or stroma cells undergo such a commutation, the terms ‘Warburg effect’ or ‘reverse Warburg effect’ were coined to describe the underlying biological phenomena. However, current in vitro systems relying on 2-D culture, single cell-type spheroids, or basal-membrane extract (BME/Matrigel)-containing 3-D structures do not thoroughly reflect these processes. Here, we aimed to establish a BME/Matrigel-free 3-D microarray cancer model to recapitulate the metabolic interplay between cancer and stromal cells that allows mechanistic analyses and drug testing. Human HT-29 colon cancer and CCD-1137Sk fibroblast cells were used in mono- and co-cultures as 2-D monolayers, spheroids, and in a cell-chip format. Metabolic patterns were studied with immunofluorescence and confocal microscopy. In chip-based co-cultures, HT-29 cells showed facilitated 3-D growth and increased levels of hexokinase-2, TP53-induced glycolysis and apoptosis regulator (TIGAR), lactate dehydrogenase, and: translocase of outer mitochondrial membrane 20 (TOMM20), when compared with HT-29 mono-cultures. Fibroblasts co-cultured with HT-29 cells expressed higher levels of mono-carboxylate transporter 4, hexokinase-2, microtubule-associated proteins 1A/1B light chain 3, and ubiquitin-binding protein p62 than in fibroblast mono-cultures, in both 2-D cultures and chips. Tetramethylrhodamin-methylester (TMRM) live-cell imaging of chip co-cultures revealed a higher mitochondrial potential in cancer cells than in fibroblasts. The findings demonstrate a crosstalk between cancer cells and fibroblasts that affects cellular growth and metabolism. Chip-based 3-D co-cultures of cancer cells and fibroblasts mimicked features of the reverse Warburg effect.

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Fernando-Macías, Ester, Maria Teresa Fernández-García, Eva García-Pérez, Belén Porrero Guerrero, Camilo López-Arévalo, Raquel Rodríguez-Uría, Sandra Sanz-Navarro, et al. "A new aggressive xenograft model of human colon cancer using cancer-associated fibroblasts." PeerJ 8 (June 3, 2020): e9045. http://dx.doi.org/10.7717/peerj.9045.

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Background Colorectal cancer is the second leading cause of cancer death. Almost half of the patients present recurrence within 5 years after the treatment of the primary tumor, the majority, with metastasis. On the other hand, in the search for new animal models that simulate metastatic cancer, it has been suggested that fibroblasts immersed in the peritumoral stroma (cancer-associated fibroblasts (CAFs)), play a relevant role in the development of cancer. The objective of this study was to identify an adequate animal model to study metastatic colon cancer and the application of new treatments. Methods Human CAFs and normal fibroblasts (NF) for transplant and culture were obtained from surgical fresh samples of patients with adenocarcinoma of sigmoid colon. Stromal cell purity was evaluated by morphology and immunostaining with vimentin (VIM) as a fibroblast marker and anti-proColXIα1 as a specific human CAF marker. Phenotypic characterization of cultured stromal cells was performed by co-staining with mesenchymal and epithelial cell markers. For identification in mice, human CAFs were labeled with the PKH26 red fluorescence dye. Cell line HT-29 was used as tumor cells. Transplant in the head of the pancreas of 34 SCID mice was performed in four different groups, as follows: I. 150,000 CAFS (n = 12), IIa. 1.5 million HT29 cells (n = 7), IIb. 150,000 NF+1.5 million HT29 cells (n = 5), III. 150,000 CAFS+1.5 million HT29 cells (n = 10). After euthanasia performed one month later, histological analysis was made using hematoxylin–eosin and anti-proColXIα1. A histopathological score system based on three features (tumor volume, desmoplasia and number of metastasized organs) was established to compare the tumor severity. Results The CAFs and NF cultured were proColXIα1+/VIM+, proColXIα1/alphaSMA+ and proColXIα1+/CK19+ in different proportions without differences among them, but the CAFs growth curve was significantly larger than that of the NF (p < 0.05). No tumor developed in those animals that only received CAFs. When comparing group II (a + b) vs. group III, both groups showed 100% hepatic metastases. Median hepatic nodules, tumor burden, lung metastases and severity score were bigger in group III vs group II (a + b), although without being significant, except in the case of the median tumor volume, that was significantly higher in group III (154.8 (76.9–563.2) mm3) vs group II (46.7 (3.7–239.6) mm3), p = 0.04. A correlation was observed between the size of the tumor developed in the pancreas and the metastatic tumor burden in the liver and with the severity score. Conclusion Our experiments demonstrate that cultured CAFs have a higher growth than NF and that when human CAFs are associated to human tumor cells, larger tumors with liver and lung metastases are generated than if only colon cancer cells with/without NF are transplanted. This emphasizes the importance of the tumor stroma, and especially the CAFs, in the development of cancer.

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Türlü, Ceylan, Nicholas Willumsen, Debora Marando, Peter Schjerling, Edyta Biskup, Jens Hannibal, Lars N. Jorgensen та Magnus S. Ågren. "A Human Cellular Model for Colorectal Anastomotic Repair: The Effect of Localization and Transforming Growth Factor-β1 Treatment on Collagen Deposition and Biomarkers". International Journal of Molecular Sciences 22, № 4 (5 лютого 2021): 1616. http://dx.doi.org/10.3390/ijms22041616.

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Anastomotic leakage (AL) is a devastating complication after colorectal surgery, possibly due to the loss of stabilizing collagen fibers in the submucosa. Our aim was to assess the formation of collagen in the colon versus the rectum with or without transforming growth factor (TGF)-β1 exposure in a human cellular model of colorectal repair. Primary fibroblasts were isolated by an explant procedure from clinically resected tissue rings during anastomosis construction in 19 consecutive colorectal patients who underwent laparoscopy. The cells, identified as fibroblasts by morphologic characteristics and flow cytometry analysis (CD90+), were cultured for 8 days and in 12 patients in the presence of 1 ng/mL TGF-β1. Total collagen deposition was measured colorimetrically after Sirius red staining of fixed cell layers, and type I, III, and VI collagen biosynthesis and degradation were specifically determined by the biomarkers PINP, PRO-C3, PRO-C6, and C3M in conditioned media by competitive enzyme-linked immunosorbent assays. Total collagen deposition by fibroblasts from the colon and rectum did not significantly differ. TGF-β1 treatment increased PINP, PRO-C6, and total collagen deposition. Mechanistically, TGF-β1 treatment increased COL1A1 and ACTA2 (encoding α-smooth muscle actin), and decreased COL6A1 and MMP2 mRNA levels in colorectal fibroblasts. In conclusion, we found no effect of anatomic localization on collagen production by fibroblasts derived from the large intestine. TGF-β1 represents a potential therapeutic agent for the prevention of AL by increasing type I collagen synthesis and collagen deposition.

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Pucilowska, Jolanta B., Kirk K. McNaughton, Nirupama K. Mohapatra, Eileen C. Hoyt, Ellen M. Zimmermann, R. Balfour Sartor та P. Kay Lund. "IGF-I and procollagen α1(I) are coexpressed in a subset of mesenchymal cells in active Crohn's disease". American Journal of Physiology-Gastrointestinal and Liver Physiology 279, № 6 (1 грудня 2000): G1307—G1322. http://dx.doi.org/10.1152/ajpgi.2000.279.6.g1307.

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This study tested the hypothesis that insulin-like growth factor I (IGF-I) expression is increased at sites of fibrosis in diseased intestine of patients with Crohn's disease (CD). IGF-I mRNA was quantified by RNase protection assay in uninvolved and involved intestine of 13 CD patients (10 ileum, 3 colon) and 7 ulcerative colitis (UC) patients (colon). In situ hybridization histochemistry compared the localization of IGF-I and procollagen α1(I) mRNAs. Masson's trichrome staining and immunohistochemistry for IGF-I precursor, α-smooth muscle actin (A), vimentin (V), desmin (D), and c- kit were used to examine the mesenchymal cell subtypes that express IGF-I and collagen in uninvolved and involved ileum and colon of CD patients and “normal” ileum and colon from noninflammatory controls. IGF-I mRNA was elevated in involved ileum and colon of patients with CD but not in involved colon of patients with UC. IGF-I and procollagen α1(I) mRNA showed overlapping distribution within fibrotic submucosa and muscularis propria of involved CD ileum and colon. In involved CD intestine, increased IGF-I precursor expression localized to mesenchymal cells in regions of tissue disorganization and fibrosis in muscularis mucosa, submucosa, and muscularis propria. In these regions, there were increased numbers of V+ cells relative to normal or uninvolved intestine. Increased IGF-I expression was localized to cells with a phenotype typical of fibroblasts (V+/A−/D−), myofibroblasts (V+/A+/D+), and, to a lesser extent, cells with normal enteric smooth muscle phenotype (V−/A+/D+). We conclude that increased IGF-I expression in multiple mesenchymal cell subtypes and increased numbers of cells with fibroblast/myofibroblast phenotype are involved in fibrosis associated with CD.

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Iozzo, R. V. "Neoplastic modulation of extracellular matrix. Colon carcinoma cells release polypeptides that alter proteoglycan metabolism in colon fibroblasts." Journal of Biological Chemistry 260, no. 12 (June 1985): 7464–73. http://dx.doi.org/10.1016/s0021-9258(17)39630-8.

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Sadowska, Beata, Joanna Rywaniak, Anna Cichocka, Kinga Cichocka, Jerzy Żuchowski, Urszula Wójcik-Bojek, Marzena Więckowska-Szakiel, and Barbara Różalska. "Phenolic and Non-Polar Fractions of the Extracts from Fruits, Leaves, and Twigs of Elaeagnus rhamnoides (L.) A. Nelson—The Implications for Human Barrier Cells." Molecules 25, no. 9 (May 9, 2020): 2238. http://dx.doi.org/10.3390/molecules25092238.

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Biological potential of plant extracts are widely described. Because their oral or topical administration is usually recommended, intestinal mucous and skin are the first surfaces exposed to such preparations. Therefore, we asked the question whether phenolic and non-polar fractions of the extracts from fruits, twigs, and leaves of sea buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) would be able to modulate the functions of human physiological barrier. The study was carried on caucasian colon epithelial-like Caco-2 cells and human foreskin fibroblasts HFF-1 line. Cell secretory activity (ELISA), the expression of cell surface molecules (flow cytometry), cell migration during wound healing in vitro (scratch assay) were assessed. It was demonstrated for the first time, that sea buckthorn extracts can improve intestinal and skin barrier by increasing of ICAM-1 expression on colon epithelial cells and intensification of IL-8 production by fibroblasts. On the other hand, an inhibition of fibroblasts migration in the presence of those preparations was noted. Therefore, greater attention should be paid on precise description of plant extracts effect depended on target cells and their role to give adequate recommendations for such preparations use.

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Seixas, Nalin, Bruno Ravanello, Ibrahim Morgan, Goran Kaluđerović, and Ludger Wessjohann. "Chlorambucil Conjugated Ugi Dendrimers with PAMAM-NH2 Core and Evaluation of Their Anticancer Activity." Pharmaceutics 11, no. 2 (February 1, 2019): 59. http://dx.doi.org/10.3390/pharmaceutics11020059.

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Herein, a new Ugi multicomponent reaction strategy is described to enhance activity and solubility of the chemotherapeutic drug chlorambucil through its conjugation to poly(amidoamine) (PAMAM-NH2) dendrimers with the simultaneous introduction of lipidic (i-Pr) and cationic (–NH2) or anionic (–COOH) groups. Standard viability assays were used to evaluate the anticancer potential of the water-soluble dendrimers against PC-3 prostate and HT-29 colon cancer cell lines, as well as non-cancerous mouse NIH3T3 fibroblasts. It could be demonstrated that the anticancer activity against PC-3 cells was considerably improved when both chlorambucil and –NH2 (cationic) groups were present on the dendrimer surface (1b). Additionally, this dendrimer showed activity only against the prostate cancer cells (PC-3), while it did not affect colon cancer cells and fibroblasts significantly. The cationic chlorambucil-dendrimer 1b blocks PC-3 cells in the G2/M phase and induces caspase independent apoptosis.

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Teijeira, Alvaro, Itziar Migueliz, Saray Garasa, Marina Bacac, Christian Klein, and Ignacio Melero. "Abstract 2887: Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2887. http://dx.doi.org/10.1158/1538-7445.am2022-2887.

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Abstract Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system. Citation Format: Alvaro Teijeira, Itziar Migueliz, Saray Garasa, Marina Bacac, Christian Klein, Ignacio Melero. Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2887.

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Møller, Trine, Jaslin P. James, Kim Holmstrøm, Flemming B. Sørensen, Jan Lindebjerg та Boye S. Nielsen. "Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer". International Journal of Molecular Sciences 20, № 8 (17 квітня 2019): 1907. http://dx.doi.org/10.3390/ijms20081907.

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MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (n = 4) with evident cancer cell budding. In all four cases, TNF-α mRNA was seen in a small subset of cancer cells at the invasive front. Evaluation of miR-21 and TNF-α mRNA expression was performed on digital slides obtained by confocal slide scanning microscopy. Both co-expression and lack of co-expression with miR-21 in the budding cancer cells was noted, suggesting non-correlated expression. miR-21 was more often seen in cancer cells than TNF-α mRNA. In conclusion, we report that miR-21 is not linked to expression of the pro-inflammatory cytokine TNF-α mRNA, but that miR-21 and TNF-α both take part in the cancer expansion at the invasive front of colon cancers. We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity.

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Li, Dandan, Zhi Liu, Xiaorong Ding, and Zhensheng Qin. "AEBP1 Is One of the Epithelial-Mesenchymal Transition Regulatory Genes in Colon Adenocarcinoma." BioMed Research International 2021 (December 12, 2021): 1–16. http://dx.doi.org/10.1155/2021/3108933.

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Epithelial-mesenchymal transition (EMT) is involved in various tumor processes, including tumorigenesis, tumor cell migration and metastasis, tumor stemness, and therapeutic resistance. Therefore, it is important to identify the genes most associated with EMT and develop them as therapeutic targets. In this work, we first analyzed EMT hallmark gene expression profiles among 10,535 pan-cancer samples from The Cancer Genome Atlas (TCGA) and divided them into EMT high and EMT low groups according to the metagene scores. Then, we identified 12 genes that were most associated with high EMT metagene score ( R > 0.9 ) in 329 colon adenocarcinoma (COAD) patients. Among them, only 4 genes (AEBP1, KCNE4, GFPT2, and FAM26E) had statistically significant differences in prognosis ( P < 0.05 ). Next, we selected AEBP1 as a candidate and showed that AEBP1 mRNA levels and EMT biomarkers strongly coexpressed in 329 COAD samples. In addition, AEBP1 was highly expressed and associated with poor clinical outcomes and prognosis in COAD patients. Finally, to explore whether AEBP1-mediated EMT was related to the tumor microenvironment (TME), we examined AEBP1 expression levels at the single-cell levels. Our results showed that AEBP1 levels were extremely high in tumor-associated fibroblasts, which may induce EMT. AEBP1 expression was also positively correlated with the expression of fibroblast biomarkers and also with EMT metascores, suggesting that AEBP1-mediated EMT may be associated with the stimulation of fibroblast activation. Therefore, AEBP1 may be a promising target for EMT inhibition, which reduces cancer metastasis and drug resistance in COAD patients.

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40

Qi, Lu, Fuyao Song, Yue Han, Ying Zhang, and Yanqing Ding. "Atractyloside targets cancer-associated fibroblasts and inhibits the metastasis of colon cancer." Annals of Translational Medicine 8, no. 21 (November 2020): 1443. http://dx.doi.org/10.21037/atm-20-1531.

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Mukaida, Naofumi, and Soichiro Sasaki. "Fibroblasts, an inconspicuous but essential player in colon cancer development and progression." World Journal of Gastroenterology 22, no. 23 (2016): 5301. http://dx.doi.org/10.3748/wjg.v22.i23.5301.

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Kim, Edward C., Shaopeng Zheng, Yingting Zhu, and Peter Lance. "Varying levels of prostanoid synthesis in fibroblasts from normal and neoplastic colon." Gastroenterology 118, no. 4 (April 2000): A54. http://dx.doi.org/10.1016/s0016-5085(00)82287-8.

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Bahn, Rebecca S., Jay C. Zeller, and Terry J. Smith. "N-butyrate increases c-erb A oncogene expression in human colon fibroblasts." Biochemical and Biophysical Research Communications 150, no. 1 (January 1988): 259–62. http://dx.doi.org/10.1016/0006-291x(88)90514-1.

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Suetsugu, Atsushi, Yosuke Osawa, Masahito Nagaki, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, and Robert M. Hoffman. "Imaging the recruitment of cancer-associated fibroblasts by liver-metastatic colon cancer." Journal of Cellular Biochemistry 112, no. 3 (February 16, 2011): 949–53. http://dx.doi.org/10.1002/jcb.23011.

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45

Welt, S., C. R. Divgi, A. M. Scott, P. Garin-Chesa, R. D. Finn, M. Graham, E. A. Carswell, A. Cohen, S. M. Larson, and L. J. Old. "Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts." Journal of Clinical Oncology 12, no. 6 (June 1994): 1193–203. http://dx.doi.org/10.1200/jco.1994.12.6.1193.

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PURPOSE To define the toxicity, imaging, and biodistribution characteristics of iodine 131-labeled monoclonal antibody F19 (131I-mAbF19). MAbF19 recognizes the fibroblast activation protein (FAP), a cell-surface glycoprotein not present in most normal tissues, but abundantly expressed by reactive stromal fibroblasts of epithelial cancers, including more than 95% of primary and metastatic colorectal carcinomas. PATIENTS AND METHODS 131I-mAbF19 was administered intravenously to 17 patients with hepatic metastases from colorectal carcinoma who were scheduled for resection of localized metastases or insertion of hepatic artery catheter for regional chemotherapy. Seven to 8 days before surgery, patients received 131I-mAbF19 at three dose levels, with at least four patients entered at each level. RESULTS No toxicity associated with intravenous 131I-mAbF19 administration was observed. Tumor images were obtained on planar and single-photon emission tomography (SPECT) scans in 15 of 17 patients with hepatic metastases, tumor-infiltrated portal lymph nodes, and/or recurrent pelvic disease. The smallest lesion visualized was 1 cm in diameter. The optimal time for tumor imaging was 3 to 5 days after 131I-mAbF19 administration. The use of image registration techniques allowed precise anatomic localization of 131I-mAbF19 accumulation. Immunohistochemical analysis of biopsy tissues showed expression of FAP in the tumor stroma (but not in normal liver) in all patients studied and confirmed that the FAP-positive tumor stromal fibroblasts were interposed between the tumor capillaries and the malignant colon epithelial cells. At the time of surgery, tumor-to-liver ratios up to 21:1 and tumor-to-serum ratios up to 9:1 were obtained. The fraction of the injected 131I-mAbF19 dose per gram tumor (%ID/g tumor) localized to hepatic metastases at the time of surgery ranged from 0.001% to 0.016%. CONCLUSION The FAP tumor fibroblast antigen is highly expressed in primary and metastatic colorectal carcinomas and shows limited expression in normal adult tissues. This highly selective expression pattern allows imaging of colorectal carcinoma lesions as small as 1 cm in diameter on 131I-mAbF19 scans. Because of the consistent presence of FAP in the stroma of epithelial cancers and the accessibility of FAP-positive tumor stromal fibroblasts to circulating monoclonal antibodies (mAbs), this study suggests possible diagnostic and therapeutic applications of humanized mAbF19 and mAbF19 constructs with novel immune and nonimmune effector functions.

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Osikov, M. V., M. S. Boyko, E. V. Simonyan, and V. A. Ushakova. "Clinical and morphological characteristics of experimental ulcerative colitis in the conditions of using original rectal suppositories with vitamin D₃." Ural Medical Journal 20, no. 1 (July 12, 2021): 8–15. http://dx.doi.org/10.52420/2071-5943-2021-20-1-8-15.

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Introduction. Vitamin D3 possesses antioxidant, anti-inflammatory, immunomodulatory, and other properties, has been shown to be effective in some autoimmune diseases, which is a prerequisite for studying its effect, when applied locally, on the clinical status and morphology of the site of injury in ulcerative colitis (UC).The aims was to study the effect of vitamin D3 in the composition of original rectal suppositories on the clinical status and morphology of the lesion of colon in experimental UC.Materials and methods. UC was modeled by two-stage administration of oxazolone. Rectal suppositories were prepared on the basis of a 10% aqueous solution of vitamin D3. The clinical status was assessed using the Disease activity index (DAI) scale. In the area of colon damage, the number of neutrophils, lymphocytes, eosinophils, histiocytes, plasmocytes and fibroblasts was examined per mm² d the tissue damage index (TDI) was calculated.Results and Discussion. In experimental UC, DAI increase an ulcerative defect is recorded in the colon, the number of neutrophils, lymphocytes, eosinophils, plasma cells, histiocytes, fibroblasts, TDI increases. The use of original rectal suppositories with vitamin D3 in experimental UC leads to a decrease in DAI, the size of the ulcer and TDI, a decrease in the infiltration of the intestinal wall by neutrophils, lymphocytes, eosinophils and plasma cells, an increase in the infiltration of histiocytes, fibroblasts.Conclusions. In experimental oxazolone-induced colitis, the clinical picture and morphology of the injury site characteristic of UC are recorded. The use of original rectal suppositories with vitamin D3 a total dose of 18,000 IU leads to a decrease in the severity of clinical signs and a decrease in the representation in the colon wall of cells involved in tissue destruction, an increase in the representation of cells mediating repair, which was reflected in a decrease in the area of the ulcer and tissue damage index , the severity of clinical signs according to DAI weakens as lymphocytes and plasma cells decrease in the area of damage to the colon, decrease in the size of the ulcer and decrease in TDI, increase in histiocytes and fibroblasts.

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Unterleuthner, Daniela, Patrick Neuhold, Katharina Schwarz, Lukas Janker, Benjamin Neuditschko, Harini Nivarthi, Ilija Crncec, et al. "Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer." Angiogenesis 23, no. 2 (October 30, 2019): 159–77. http://dx.doi.org/10.1007/s10456-019-09688-8.

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Abstract WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.

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Gown, A. M., A. M. Vogel, D. Gordon, and P. L. Lu. "A smooth muscle-specific monoclonal antibody recognizes smooth muscle actin isozymes." Journal of Cell Biology 100, no. 3 (March 1, 1985): 807–13. http://dx.doi.org/10.1083/jcb.100.3.807.

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Injection of chicken gizzard actin into BALB/c mice resulted in the isolation of a smooth muscle-specific monoclonal antibody designated CGA7. When assayed on methanol-Carnoy's fixed, paraffin-embedded tissue, it bound to smooth muscle cells and myoepithelial cells, but failed to decorate striated muscle, endothelium, connective tissue, epithelium, or nerve. CGA7 recognized microfilament bundles in early passage cultures of rat aortic smooth muscle cells and human leiomyosarcoma cells but did not react with human fibroblasts. In Western blot experiments, CGA7 detected actin from chicken gizzard and monkey ileum, but not skeletal muscle or fibroblast actin. Immunoblots performed on two-dimensional gels demonstrated that CGA7 recognizes gamma-actin from chicken gizzard and alpha- and gamma-actin from rat colon muscularis. This antibody was an excellent tissue-specific smooth muscle marker.

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Zhang, Xiaohui, Depeng Li, Jianzhong Qin, Yaozhong Xu, and Kedong Ma. "Synthesis of 4-thio-5-(2′′-thienyl)uridine and cytotoxicity activity against colon cancer cells in vitro." RSC Advances 6, no. 74 (2016): 70099–105. http://dx.doi.org/10.1039/c6ra14356c.

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Prendecka-Wróbel, Monika, Dominika Pigoń-Zając, Magdalena Jaszek, Anna Matuszewska, Dawid Stefaniuk, Grzegorz Opielak, Katarzyna Piotrowska, Mansur Rahnama-Hezavah, and Teresa Małecka-Massalska. "Electric Cell-Substrate Impedance Sensing (ECIS) as a Convenient Tool to Assess the Potential of Low Molecular Fraction Derived from Medicinal Fungus Cerrena unicolor in Action on L929 and CT-26 Cell Lines." Molecules 27, no. 19 (September 22, 2022): 6251. http://dx.doi.org/10.3390/molecules27196251.

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The increase in the incidence of cancer has contributed to the search for new therapeutic methods. In recent years, the use of preparations of natural origin from medical fungi has increased. One such active substance is the extracellular, low molecular active fraction obtained from the medicinal fungus Cerrena unicolor. This study aimed to monitor the pharmacokinetics of different concentrations of substances isolated from the medicinal fungus Cerrena unicolor (ex-LMS) using the ECIS technique. In the study, mouse L929 fibroblasts and colon cancer CT26 cell lines were treated with different concentrations of the active fractions obtained from Cerrena unicolor: C1 = 2.285 (μg/mL); C2 = 22.85 (μg/mL); and C3 = 228.5 (μg/mL). This study demonstrated that the tested preparation from Cerrena unicolor had no considerable effect on the resistance, capacitance, and impedance of L929 fibroblast cells, which was an indicator of no significant effect on its physiological processes. At the same time, those parameters exhibited a decrease in colon cancer cell viability. Following our previous and current studies on Cerrena unicolor, ex-LMS extracts can be safely used in anticancer therapy or chemoprevention with no significant harmful effects on normal cells.

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