Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

AbstractCD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

Download Full-text

Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts

Cancers ◽

10.3390/cancers13081987 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1987

Author(s):

Eleni Mavrogonatou ◽

Adamantia Papadopoulou ◽

Asimina Fotopoulou ◽

Stathis Tsimelis ◽

Heba Bassiony ◽

...

Keyword(s):

Breast Cancer ◽

Ionizing Radiation ◽

Cancer Progression ◽

Breast Cancer Cell Lines ◽

Phenotypic Trait ◽

Mrna Levels ◽

Human Breast ◽

Down Regulation ◽

Stromal Fibroblasts ◽

Poor Prognostic Factor

Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment.

Download Full-text

Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

Nature Communications ◽

10.1038/s41467-021-21865-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maria Hurskainen ◽

Ivana Mižíková ◽

David P. Cook ◽

Noora Andersson ◽

Chanèle Cyr-Depauw ◽

...

Keyword(s):

Single Cell ◽

Lung Development ◽

Alveolar Epithelium ◽

Cell Types ◽

Capillary Endothelium ◽

Stromal Fibroblasts ◽

Main Driver ◽

Macrophage Populations ◽

Induced Changes ◽

Cellular Compartments

AbstractDuring late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.

Download Full-text

Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.

Endocrine Related Cancer ◽

10.1677/erc.0.0090045 ◽

2002 ◽

pp. 45-59 ◽

Cited By ~ 151

Author(s):

K W Colston ◽

C M√∏rk Hansen

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Bone Mineralization ◽

Active Form ◽

Cell Types ◽

Cell Cycle Regulators ◽

Dihydroxyvitamin D ◽

Cell Growth And Differentiation ◽

Regulatory Effects ◽

Apoptotic Effects

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

Download Full-text

Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.2 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 41

Author(s):

Esak Lee ◽

Niranjan B. Pandey ◽

Aleksander S. Popel

Keyword(s):

Endothelial Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Tumour Growth ◽

Tumour Progression ◽

Lymphatic Vessels ◽

Cell Types ◽

Malignant Cell ◽

Lymphatic Endothelial Cells ◽

Tumour Blood

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.

Download Full-text

The Role of Cancer-associated Fibroblasts in Tumorigenesis of Gastric Cancer

Current Pharmaceutical Design ◽

10.2174/1381612824666180601094056 ◽

2018 ◽

Vol 24 (28) ◽

pp. 3297-3302 ◽

Cited By ~ 3

Author(s):

Zhilong Ma ◽

Min Chen ◽

Xiaohu Yang ◽

Bin Xu ◽

Zhenshun Song ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Tumor Biology ◽

Vital Role ◽

Cancer Associated Fibroblasts ◽

Gastric Cancer Cells ◽

Stromal Fibroblasts ◽

Tumor Microenvironments ◽

Tumorigenesis And Progression

Cancer-associated fibroblasts (CAFs) are an important cell type present in solid tumor microenvironments, including that of gastric cancer. They play a vital role in the promotion of tumorigenesis, angiogenesis, and cancer progression through paracrine signaling and modulation of the extracellular matrix. However, the exact molecular mechanism underlying the interaction between gastric cancer cells and stromal fibroblasts remains poorly understood. Recent studies have demonstrated that various factors, such as gene and microRNA variations, are involved in this process. This review discusses recent advances in understanding how these factors are regulated in CAFs and how they affect tumor biology, which may improve our understanding of their role in gastric cancer tumorigenesis and progression and provide new promising targets for therapeutic strategies.

Download Full-text

Sp1-Induced Upregulation of LBX2-AS1 Aggravates The Progression of Glioblastoma By Targeting The miR-491-5p/LIF Axis

10.21203/rs.3.rs-242079/v1 ◽

2021 ◽

Author(s):

Wentao Li ◽

Ismatullah Soufiany ◽

Xiao Lyu ◽

Lin Zhao ◽

Chenfei Lu ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Stat3 Signaling ◽

Regulatory Effects

Abstract Background: Mounting evidences have shown the importance of lncRNAs in tumorigenesis and cancer progression. LBX2-AS1 is an oncogenic lncRNA that has been found abnormally expressed in gastric cancer and lung cancer samples. Nevertheless, the biological function of LBX2-AS1 in glioblastoma (GBM) and potential molecular mechanism are largely unclear. Methods: Relative levels of LBX2-AS1 in GBM samples and cell lines were detected by qRT-PCR and FISH. In vivo and in vitro regulatory effects of LBX2-AS1 on cell proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis in GBM were examined through xenograft models and functional experiments, respectively. The interaction between Sp1 and LBX2-AS1 was assessed by ChIP. Through bioinformatic analyses, dual-luciferase reporter assay, RIP and Western blot, the regulation of LBX2-AS1 and miR-491-5p on the target gene leukemia Inhibitory factor (LIF) was identified. Results: LBX2-AS1 was upregulated in GBM samples and cell lines, and its transcription was promoted by binding to the transcription factor Sp1. As a lncRNA mainly distributed in the cytoplasm, LBX2-AS1 upregulated LIF, and activated the LIF/STAT3 signaling by exerting the miRNA sponge effect on miR-491-5p, thus promoting cell proliferation, EMT and angiogenesis in GBM. Besides, LBX2-AS1 was unfavorable to the progression of glioma and the survival. Conclusion: Upregulated by Sp1, LBX2-AS1 promotes the progression of GBM by targeting the miR-491-5p/LIF axis. It is suggested that LBX2-AS1 may be a novel diagnostic biomarker and therapeutic target of GBM.

Download Full-text

Single-cell analysis revealed that IL4I1 promoted ovarian cancer progression

Journal of Translational Medicine ◽

10.1186/s12967-021-03123-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hongyu Zhao ◽

Yu Teng ◽

Wende Hao ◽

Jie Li ◽

Zhefeng Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Single Cell ◽

Cancer Progression ◽

Cox Regression ◽

Single Cell Analysis ◽

Cell Types ◽

In Vitro Assays ◽

Migration And Invasion ◽

Dominant Type

Abstract Background Ovarian cancer was one of the leading causes of female deaths. Patients with OC were essentially incurable and portends a poor prognosis, presumably because of profound genetic heterogeneity limiting reproducible prognostic classifications. Methods We comprehensively analyzed an ovarian cancer single-cell RNA sequencing dataset, GSE118828, and identified nine major cell types. Relationship between the clusters was explored with CellPhoneDB. A malignant epithelial cluster was confirmed using pseudotime analysis, CNV and GSVA. Furthermore, we constructed the prediction model (i.e., RiskScore) consisted of 10 prognosis-specific genes from 2397 malignant epithelial genes using the LASSO Cox regression algorithm based on public datasets. Then, the prognostic value of Riskscore was assessed with Kaplan–Meier survival analysis and time-dependent ROC curves. At last, a series of in-vitro assays were conducted to explore the roles of IL4I1, an important gene in Riskscore, in OC progression. Results We found that macrophages possessed the most interaction pairs with other clusters, and M2-like TAMs were the dominant type of macrophages. C0 was identified as the malignant epithelial cluster. Patients with a lower RiskScore had a greater OS (log-rank P < 0.01). In training set, the AUC of RiskScore was 0.666, 0.743 and 0.809 in 1-year, 3-year and 5-year survival, respectively. This was also validated in another two cohorts. Moreover, downregulation of IL4I1 inhibited OC cells proliferation, migration and invasion. Conclusions Our work provide novel insights into our understanding of the heterogeneity among OCs, and would help elucidate the biology of OC and provide clinical guidance in prognosis for OC patients.

Download Full-text

A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine

10.1101/2020.11.06.371609 ◽

2020 ◽

Author(s):

Reegan J. Willms ◽

Jennifer C. Hocking ◽

Edan Foley

Keyword(s):

Transcriptional Activity ◽

Cell Types ◽

Cellular Heterogeneity ◽

Host Responses ◽

Cellular Specificity ◽

Direct Growth ◽

A Cell ◽

Microbe Interactions ◽

Regulatory Effects ◽

Host Microbe Interactions

ABSTRACTGut microbial products direct growth, differentiation and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence, or absence, of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome, that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered transduction of vascular endothelial growth factor-dependent signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type.

Download Full-text

Exosomale microRNA-21 Promotes Keloid Fibroblast Proliferation and Collagen Production by inhibiting Smad7

Journal of Burn Care & Research ◽

10.1093/jbcr/irab116 ◽

2021 ◽

Author(s):

Qijie Li ◽

Lu Fang ◽

Junjie Chen ◽

Siqi Zhou ◽

Kai Zhou ◽

...

Keyword(s):

Normal Skin ◽

Cell Types ◽

Skin Fibroblasts ◽

Fibroblast Proliferation ◽

Collagen Production ◽

Protein Levels ◽

Keloid Fibroblast ◽

Collagen Iii ◽

Smad3 Protein ◽

Keloid Fibroblasts

Abstract In keloid fibroblasts, microRNA-21 (miR-21) enhances activation of the TGF-β–Smad-signaling pathway by downregulating Smad7 expression, thereby promoting keloid fibroblast proliferation and collagen production. However, it is unclear whether miR-21 performs the above-mentioned functions through exosomal transport. Here, we extracted exosomes from the culture supernatants of keloid and normal skin fibroblasts, and observed that exosomes from both cell types secreted exosomes; however, keloid fibroblasts secreted significantly more exosomal miR-21 than normal skin fibroblasts (P < 0.001). Interestingly, we also observed that exosomal miR-21 could enter target keloid fibroblasts. In addition, inhibiting exosomal miR-21 upregulated Smad7 protein expression and reduced Smad2 and Smad3 protein levels in target keloid fibroblasts. Furthermore, inhibiting exosomal miR-21 downregulated collagen I and collagen III expression in target keloid fibroblasts, increased the proportion of apoptotic cells, and reduced cell proliferation. Taken together, these results show that exosomal miR-21 promoted proliferation and collagen production in keloid fibroblasts by inhibiting Smad7. Thus, we identified regulatory roles for miR-21 in promoting keloid fibroblast proliferation and participating in keloid formation and development. These findings imply that miR-21 may serve as a novel target for controlling the development of keloids.

Download Full-text

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

Cancers ◽

10.3390/cancers12010029 ◽

2019 ◽

Vol 12 (1) ◽

pp. 29 ◽

Cited By ~ 3

Author(s):

Jyun-Yuan Huang ◽

Yen-Yun Wang ◽

Steven Lo ◽

Ling-Ming Tseng ◽

Dar-Ren Chen ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Progression ◽

Human Breast Cancer ◽

Breast Cancer Progression ◽

Akt Pathway ◽

Adipose Derived Stem Cells ◽

Human Breast ◽

Akt Inhibitor ◽

Promoting Effect

Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.

Download Full-text