Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting

Sung, Shian Ying; Chung, Leland W.K.

doi:10.1046/j.1432-0436.2002.700905.x

Cited by 123 publications

(86 citation statements)

References 121 publications

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“…Based on the well-established reciprocal cellular interaction between prostate cancer cells, cancer-associated stroma and tumor endothelium, this cotargeting approach has the potential to inhibit cancer growth, progression and metastasis. 6,34 Results from our studies provide further evidence that cotargeting tumor cells along with the tumor microenvironment is more effective and yields a more durable response than targeting a single-cell compartment.…”

Section: Discussionmentioning

confidence: 66%

“…Wellestablished autocrine, paracrine and endocrine communication loops exist between cancer cells and their adjacent cellular components, 6 including (1) smooth muscle cells and fibroblasts, which provide critical soluble growth factors and extracellular matrices (ECMs) that support tumor growth, survival and differentiation; (2) endothelial cells, which form critical blood vessels, supply oxygen and nutrients to the tumor epithelium, and remove metabolic wastes from the tumor cells; (3) inflammatory cells, which could support important cytokines to defend against bacterial infection of the tumor epithelium and also potentially maintain the growth requirements of tumor cells. Using an experimental coculture cell model and chimeric tumor model 7 comprised of human prostate cancer and bone stromal cells to mimic a functional prostate organoid, our laboratory designed a strategy cotargeting both tumor and its supporting stroma.…”

mentioning

confidence: 99%

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Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

et al. 2004

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Tumor-endothelial interaction contributes to local prostate tumor growth and distant metastasis. In this communication, we designed a novel approach to target both cancer cells and their ''crosstalk'' with surrounding microvascular endothelium in an experimental hormone refractory human prostate cancer model. We evaluated the in vitro and in vivo synergistic and/or additive effects of a combination of conditional oncolytic adenovirus plus an adenoviral-mediated antiangiogenic therapy. In the in vitro study, we demonstrated that human umbilical vein endothelial cells (HUVEC) and human C4-2 androgen-independent (AI) prostate cancer cells, when infected with an antiangiogenic adenoviral (Ad)-Flk1-Fc vector secreting a soluble form of Flk1, showed dramatically inhibited proliferation, migration and tubular formation of HUVEC endothelial cells. C4-2 cells showed maximal growth inhibition when coinfected with Ad-Flk1-Fc and Ad-hOC-E1, a conditional replication-competent Ad vector with viral replication driven by a human osteocalcin (hOC) promoter targeting both prostate cancer epithelial and stromal cells. Using a threedimensional (3D) coculture model, we found that targeting C4-2 cells with Ad-hOC-E1 markedly decreased tubular formation in HUVEC, as visualized by confocal microscopy. In a subcutaneous C4-2 tumor xenograft model, tumor volume was decreased by 40-60% in animals treated with Ad-Flk1-Fc or Ad-hOC-E1 plus vitamin D 3 alone and by 90% in a combined treatment group, compared to untreated animals in an 8-week treatment period. Moreover, three of 10 (30%) pre-established tumors completely regressed when animals received combination therapy. Cotargeting tumor and tumor endothelium could be a promising gene therapy strategy for the treatment of both localized and metastatic human prostate cancer.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

et al. 2004

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“…[71][72][73][74] However, these effects are mainly thought to be mediated by the expression of cytokines and growth factors by the cancer-associated fibroblasts/inflammatory cells and it is unlikely that the proliferative activity of these cells per se has a significant role in these processes. We are aware that the ultimate test to determine whether the low-grade carcinomas with cellular, proliferative stroma and increased Recurrence Score do worse than those without these features would be longterm patient outcome.…”

Section: Discussionmentioning

confidence: 99%

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

et al. 2012

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Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score o18 (low risk) were compared with those with Recurrence Score Z18 (intermediate/high risk). Carcinomas associated with Recurrence Score Z18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score Z18. A Ki-67-positive stromal/ tumor cells ratio of 41 predicted Recurrence Score Z18 with an area under the curve of 0.8967 on receiver operator curve analysis (Po0.0001). Our results suggest that the presence of increased stromal cellularity and/ or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

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“…12,13 Many research groups have also shown that a dynamic stromal-epithelial interaction plays a critical role in the progression and metastasis of PCa. [14][15][16][17][18][19][20] Growth factors play a central role in mediating the interactions between epithelial and stromal cells. 21 The stromal-epithelial interaction is also critical for mediating the effects of these molecules on epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

Jiang

Han²,

Zhao³

et al. 2011

Asian J Androl

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It is well known that prostate cancer (PCa) occurs predominantly in the peripheral zone (PZ), whereas benign prostatic hyperplasia (BPH) typically develops in the transition zone. To identify possible mechanisms underlying zonal differences, we compared the effects of prostate stromal cells derived from the peripheral zone (PZsc) and the transition zone (TZsc) on a PCa epithelial cell line (PC3) in the presence of sex hormones. First, we observed that androgen receptor (AR) mRNA was more highly expressed in PZsc than TZsc when the cells were treated with dihydrotestosterone (DHT) and b-oestradiol (E2) (P,0.05). By ELISA, we looked for differences in the secretion of peptide growth factors from PZsc and TZsc. We found that keratinocyte growth factor (KGF) secretion increased with increasing concentrations of DHT (P,0.01) and was higher in PZsc than TZsc. Under treatment with DHT plus E2, PZsc secreted more transforming growth factor-b1 (TGF-b1) than TZsc, but this pattern was reversed when the cells were treated with E2 only. With increasing concentrations of DHT, insulin-like growth factor-1 (IGF-1) secretion increased in PZsc but decreased in TZsc. To further characterize the effects of PZsc and TZsc on PC3 cells, we developed a coculture model and performed MTT assays, Western blot analysis and real-time RT-PCR. We found that PZsc promoted PC3 cell proliferation and progression better than TZsc, particularly when treated with 10 nmol l 21 DHT plus 10 nmol l 21 E2. In conclusion, our data suggest that PZsc may have a greater capacity to induce PCa development and progression than TZsc via growth factors regulated by sex hormones. These findings provide possible mechanisms underlying zonal differences in prostate diseases, which may aid the search for novel therapeutic targets for PCa.

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Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting

Cited by 123 publications

References 121 publications

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

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