Osteolytic cancer cells induce vascular/axon guidance processes in the bone/bone marrow stroma

Hensel, Janine; Wetterwald, Antoinette; Temanni, Ramzi; Keller, Irene; Riether, Carsten; Pluijm, Gabri van der; Cecchini, Marco; Thalmann, George N.

doi:10.18632/oncotarget.25608

Cited by 9 publications

(7 citation statements)

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“…The BZW2 gene affects osteosarcoma in human cell lines by accelerating bone tumor growth (Cheng et al, 2017). The EFNA5 gene was highly expressed in osteolytic human prostate or breast cancer cells that were inoculated into the bone marrow cavity of the tibial bones of immunocompromised mice (Hensel et al, 2018). Overexpression of USP45 inhibits osteogenesis or formation of new bone in human patients with glucocorticoid-induced osteonecrosis of the femoral head (Kuang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Exploring physiological and genetic variation of digital cushion thickness in Holstein and Jersey cows and bulls

Stambuk

Staiger

Heins

et al. 2020

Journal of Dairy Science

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The objectives of our study were to expand phenotypic characterization of digital cushion thickness (DCT) to the Jersey breed and include mature bulls and to identify breed-specific quantitative trait loci (QTL) for DCT within the Jersey or Holstein breeds and common QTL across breeds and sexes to better understand biological regulation and guide future use of marker-assisted selection. In a cohort of 698 cows and 85 bulls (Holstein and Jersey) from 8 farms in New York State, data were collected on DCT, body condition score (BCS), withers height, and sacral height. All animals underwent sonographic examination of the digital cushion evaluated at the sole ulcer site for the right front and hind feet. Linear mixed models were conducted on DCT separately for cows and bulls with fixed effects of time point, breed, age, digit, and BCS group. The models included random effects to control for the random subset of animals per farm, repeated measures, and multiple measurements from each animal. The phenotypic results indicated that DCT varied by time point, breed, age, digit, and BCS group for cows and by breed, age, digit, and BCS group for bulls. For the genotypic study, 616 cow DNA samples were genotyped on the Illumina BovineHD 777K BeadChip (Illumina Inc., San Diego, CA), whereas 76 bull DNA samples were genotyped on different platforms ranging from 5K to 150K. Multiple genome-wide association studies were conducted to highlight pertinent phenotyping parameters and genetic markers for genomic selection. Data were separated into 8 data sets based on different combinations of breed and sex. Each data set was assessed for quality of markers and samples before conducting genome-wide association studies for DCT, testing the inheritance models and genetic variation of digit, foot, and average thickness. Ten markers passed the Bonferroni correction threshold and 9 passed false discovery rate from 10 genome-wide association studies using a combination of the covariates breed, sex, genotyping batch plate, age, BCS, withers height, and sacral height. Of the 43 candidate genes, 8 novel biologically plausible genes were identified on Bos taurus autosomes 3, 4, 7, and 9: SFRS18 and LRRFIP1 function in fat deposition, whereas AHR, BZW2, EFNA5, USP45, and VAV3 effect bone growth, and SOSTDC1 is related to epidermal keratinocyte function. The genetic markers associated with DCT in this study were explored for variation between cows and bulls within and across breeds for their potential use in marker-assisted selection.

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Section: Discussionmentioning

confidence: 99%

Exploring physiological and genetic variation of digital cushion thickness in Holstein and Jersey cows and bulls

Stambuk

Staiger

Heins

et al. 2020

Journal of Dairy Science

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“…In contrast, the stromal signature of osteolytic PCa metastasis (PC-3 cell xenografts) is uniquely enriched in genes involved in vascular/axon guidance [169]. Distinct vessel morphology and the presence of vascular smooth muscle cells and mesenchymal stem cells expressing bone osteolytic factors indicate the requirement for a different metastatic niche compared to the osteoblastic stroma signature [169]. However, even in this context CAFs may play a relevant role, since intracardial inoculation of osteolytic PC-3 cells secreting IL-1β induces FSP-1 expression, a typical CAF marker, in mouse bone stromal cells [53].…”

Section: Role Of Cafs In Pca Bone Metastasismentioning

confidence: 99%

“…Among these genes, ASPN and POSTN expression has been observed also in CAFs from human bone metastatic and primary PCa ( Figure 3 B), highlighting the translational and prognostic value of these genes [ 44 ]. In contrast, the stromal signature of osteolytic PCa metastasis (PC-3 cell xenografts) is uniquely enriched in genes involved in vascular/axon guidance [ 169 ]. Distinct vessel morphology and the presence of vascular smooth muscle cells and mesenchymal stem cells expressing bone osteolytic factors indicate the requirement for a different metastatic niche compared to the osteoblastic stroma signature [ 169 ].…”

Section: Stroma In Pca Bone Metastasismentioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Bonollo

Thalmann

Julio

et al. 2020

Cancers

Self Cite

105

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Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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“…Studies have shown that cancer cell growth competes for the hematopoietic niche in the bone marrow with the normal residing stem cells [ 3 ], and depending on the cancer cell phenotype, this may lead to either osteoblastic or osteolytic lesions. The stroma signature of osteolytic PCa cells (PC-3) xenografted intraosseously in immunocompromised mice induce a vascular/axon guidance signature [ 4 ]. The stroma signature of osteoblastic lesions from human VCap and C4-2B PCa cell lines indicated an enrichment of the hematopoietic and prostate epithelial stem cell niche.…”

Section: Introductionmentioning

confidence: 99%

Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures

Karkampouna

Filippo

et al. 2020

Cancers

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Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential.

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Osteolytic cancer cells induce vascular/axon guidance processes in the bone/bone marrow stroma

Cited by 9 publications

References 50 publications

Exploring physiological and genetic variation of digital cushion thickness in Holstein and Jersey cows and bulls

Exploring physiological and genetic variation of digital cushion thickness in Holstein and Jersey cows and bulls

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures

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