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Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape.

ABSTRACT: The metastatic invasion of cancer cells from primary tumors to distant ecological niches, rather than the primary tumors, is the cause of much cancer mortality [Zhang QB, et al. (2010) Int J Cancer 126:2534-2541; Chambers AF, Goss PE (2008) Breast Cancer Res 10:114]. Metastasis is a three-dimensional invasion process where cells spread from their site of origin and colonize distant microenvironmental niches. It is critical to be able to assess quantitatively the metastatic potential of cancer cells [Harma V, et al. (2010) PLoS ONE 5:e10431]. We have constructed a microfabricated chip with a three-dimensional topology consisting of lowlands and isolated square highlands (Tepuis), which stand hundreds of microns above the lowlands, in order to assess cancer cell metastatic potential as they invade the highlands. As a test case, the invasive ascents of the Tepui by highly metastatic PC-3 and noninvasive LNCaP prostate cancer cells were used. The vertical ascent by prostate cancer cells from the lowlands to the tops of the Tepui was imaged using confocal microscopy and used as a measure of the relative invasiveness. The less-metastatic cells (LNCaP) never populated all available tops, leaving about 15% of them unoccupied, whereas the more metastatic PC-3 cells occupied all available Tepuis. We argue that this distinct difference in invasiveness is due to contact inhibition.

SUBMITTER: Liu L

PROVIDER: S-EPMC3084062 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape.

Liu Liyu L Sun Bo B Pedersen Jonas N JN Aw Yong Koh-Meng KM Getzenberg Robert H RH Stone Howard A HA Austin Robert H RH

Proceedings of the National Academy of Sciences of the United States of America 20110407 17

The metastatic invasion of cancer cells from primary tumors to distant ecological niches, rather than the primary tumors, is the cause of much cancer mortality [Zhang QB, et al. (2010) Int J Cancer 126:2534-2541; Chambers AF, Goss PE (2008) Breast Cancer Res 10:114]. Metastasis is a three-dimensional invasion process where cells spread from their site of origin and colonize distant microenvironmental niches. It is critical to be able to assess quantitatively the metastatic potential of cancer ce ...[more]

PMID: 21474778

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Project description:BackgroundProstate cancer (PCa) cells preferentially metastasize to bone at least in part by acquiring osteomimetic properties. Runx2, an osteoblast master transcription factor, is aberrantly expressed in PCa cells, and promotes their metastatic phenotype. The transcriptional programs regulated by Runx2 have been extensively studied during osteoblastogenesis, where it activates or represses target genes in a context-dependent manner. However, little is known about the gene regulatory networks influenced by Runx2 in PCa cells. We therefore investigated genome wide mRNA expression changes in PCa cells in response to Runx2.ResultsWe engineered a C4-2B PCa sub-line called C4-2B/Rx2 dox, in which Doxycycline (Dox) treatment stimulates Runx2 expression from very low to levels observed in other PCa cells. Transcriptome profiling using whole genome expression array followed by in silico analysis indicated that Runx2 upregulated a multitude of genes with prominent cancer associated functions. They included secreted factors (CSF2, SDF-1), proteolytic enzymes (MMP9, CST7), cytoskeleton modulators (SDC2, Twinfilin, SH3PXD2A), intracellular signaling molecules (DUSP1, SPHK1, RASD1) and transcription factors (Sox9, SNAI2, SMAD3) functioning in epithelium to mesenchyme transition (EMT), tissue invasion, as well as homing and attachment to bone. Consistent with the gene expression data, induction of Runx2 in C4-2B cells enhanced their invasiveness. It also promoted cellular quiescence by blocking the G1/S phase transition during cell cycle progression. Furthermore, the cell cycle block was reversed as Runx2 levels declined after Dox withdrawal.ConclusionsThe effects of Runx2 in C4-2B/Rx2 dox cells, as well as similar observations made by employing LNCaP, 22RV1 and PC3 cells, highlight multiple mechanisms by which Runx2 promotes the metastatic phenotype of PCa cells, including tissue invasion, homing to bone and induction of high bone turnover. Runx2 is therefore an attractive target for the development of novel diagnostic, prognostic and therapeutic approaches to PCa management. Targeting Runx2 may prove more effective than focusing on its individual downstream genes and pathways.

Project description:BackgroundThis study was to explore the infiltration pattern of immune cells in the prostate cancer (PCa) microenvironment and evaluate the possibility of specific infiltrating immune cells as potential prognostic biomarkers in PCa.MethodsInfiltrating percentage of 22 immune cells were extracted from 27 normalized datasets by CIBERSORT algorithm. Samples with CIBERSORT p-value < 0.05 were subsequently merged and divided into normal or tumor groups. The differences of 22 immune cells between normal and tumor tissues were analyzed along with potential infiltrating correlations among 22 immune cells and Gleason grades. SNV data from TCGA was used to calculate the TMB score. A univariate and multivariate regression were used to evaluate the prognostic effects of immune cells in PCa.ResultsTen immune cells with significant differences were identified, including seven increased and three decreased infiltrating immune cells from 190 normal prostate tissues and 537 PCa tissues. Among them, the percentage of infiltration of resting NK cells increased the most, whereas the percentage of infiltration of resting mast cells decreased the most. In normal tissues, CD8+ T cells had the strongest infiltrating correlation with monocytes, while activated NK cells and naive B cells were the highest in PCa tissues. Moreover, the infiltration of five immune cells was significantly associated with TMB score and mutations of immune gene change the infiltration of immune cells. The Area Under Curve (AUC) of the multivariate regression model for the five- and 10-year survival prediction of PCa reached 0.796 and 0.862. The validation cohort proved that the model was reproducible.ConclusionsThis study demonstrated that different infiltrating immune cells in prostate cancer, especially higher infiltrating M1 macrophages and neutrophils in PCa tissue, are associated with patients' prognosis, suggesting that these two immune cells might be potential targets for PCa diagnosis and prognosis of treatment.

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Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape.

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Probing the invasiveness of prostate cancer cells in a 3D microfabricated landscape.

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