Prostate cancer with disseminated carcinomatosis of the bone marrow: Two case reports

AbstractCancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

Download Full-text

Long non‐coding RNA NORAD promotes the prostate cancer cell extracellular vesicle release via microRNA-541-3p-regulated PKM2 to induce bone metastasis of prostate cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01891-0 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Chuan-yi Hu ◽

Juan Chen ◽

Xin-hua Qin ◽

Pan You ◽

Jie Ma ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Downstream Target ◽

Non Coding Rna ◽

Target Molecules ◽

Long Non Coding Rna

Abstract Background Bone metastasis is the leading cause of mortality and reduced quality of life in patients with metastatic prostate cancer (PCa). Long non-coding RNA activated by DNA damage (NORAD) has been observed to have an abnormal expression in various cancers. This article aimed to explore the molecular mechanism underlying the regulatory role of NORAD in bone metastasis of PCa. Methods NORAD expression in clinical PCa tissues and cell lines was detected with the application of qRT-PCR. Cancer cells were then transfected with plasmids expressing NORAD, after which Transwell assay and CCK-8 assay were carried out to detect proliferation, migration, and bone metastasis of PCa. NORAD downstream target molecules were screened through bioinformatics analysis, followed by further verification using dual luciferase assay. Extracellular vesicles (EVs) were labeled with PKH67 and interacted with bone marrow stromal cells. The gain- and loss-function method was applied to determine the internalization and secretion of PCa cells-derived EVs under the intervention of downstream target molecules or NORAD. Results PCa tissues and cell lines were observed to have a high expression of NORAD, particularly in tissues with bone metastasis. NORAD knockdown resulted in reduced secretion and internalization of EVs, and suppressed proliferation, migration, and bone metastasis of PCa cells. It was indicated that NORAD interacted with miR-541-3p, leading to the upregulation of PKM2. Forced expression of PKM2 promoted the transfer of PKH67-labeled EVs to bone marrow stromal cells. Conclusions NORAD might serve as a ceRNA of miR-541-3p to promote PKM2 expression, thereby enhancing the development of bone metastasis in PCa by promoting internalization and transfer of EVs of cancer cells, providing an insight into a novel treatment for the disorder.

Download Full-text

Perioperative Activation of Disseminated Tumor Cells in Bone Marrow of Patients With Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.0563 ◽

2009 ◽

Vol 27 (10) ◽

pp. 1549-1556 ◽

Cited By ~ 112

Author(s):

Dorothea Weckermann ◽

Bernhard Polzer ◽

Thomas Ragg ◽

Andreas Blana ◽

Günter Schlimok ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Tumor Cells ◽

Cox Regression ◽

Systemic Disease ◽

Disseminated Tumor Cells ◽

Comparative Genomic ◽

Prognostic Impact ◽

Primary Tumors ◽

Cox Regression Analysis

Purpose The outcome of prostate cancer is highly unpredictable. To assess the dynamics of systemic disease and to identify patients at high risk for early relapse we followed the fate of disseminated tumor cells in bone marrow for up to 10 years and genetically analyzed such cells isolated at various stages of disease. Patients and Methods Nine hundred bone marrow aspirates from 384 patients were stained using the monoclonal antibody A45-B/B3 directed against cytokeratins 8, 18, and 19. Log-rank statistics and Cox regression analysis were applied to determine the prognostic impact of positive cells detected before surgery (244 patients) and postoperatively (214 patients). Samples from primary tumors (n = 55) and single disseminated tumor cells (n = 100) were analyzed by comparative genomic hybridization. Results Detection of cytokeratin-positive cells before surgery was the strongest independent risk factor for metastasis within 48 months (P < .001; relative risk [RR], 5.5; 95% CI, 2.4 to 12.9). In contrast, cytokeratin-positive cells detected 6 months to 10 years after radical prostatectomy were consistently present in bone marrow with a prevalence of approximately 20% but had no influence on disease outcome. Characteristic genotypes of cytokeratin-positive cells were selected at manifestation of metastasis. Conclusion Cytokeratin-positive cells in the bone marrow of prostate cancer patients are only prognostically relevant when detected before surgery. Because we could not identify significant genetic differences between pre- and postoperatively isolated tumor cells before manifestation of metastasis, we postulate the existence of perioperative stimuli that activate disseminated tumor cells. Patients with cytokeratin-positive cells in bone marrow before surgery may therefore benefit from adjuvant therapies.

Download Full-text

Prostate Cancer Cell Adhesion to Bone Marrow Endothelium

Cancer Research ◽

10.1158/0008-5472.can-03-3487 ◽

2004 ◽

Vol 64 (6) ◽

pp. 2083-2089 ◽

Cited By ~ 23

Author(s):

Victor I. Romanov ◽

Terry Whyard ◽

Howard L. Adler ◽

Wayne C. Waltzer ◽

Stanley Zucker

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Cell Adhesion ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Adhesion

Download Full-text

Treatment of Cancer and Inflammation With Low-Dose Ionizing Radiation

Dose-Response ◽

10.1177/1559325817697531 ◽

2017 ◽

Vol 15 (1) ◽

pp. 155932581769753 ◽

Cited By ~ 18

Author(s):

Shuji Kojima ◽

Mitsutoshi Tsukimoto ◽

Noriko Shimura ◽

Hironobu Koga ◽

Akishisa Murata ◽

...

Keyword(s):

Prostate Cancer ◽

Ulcerative Colitis ◽

Bone Metastasis ◽

Low Dose ◽

Case Reports ◽

Low Dose Radiation ◽

X Ray ◽

Radiation Hormesis ◽

Irradiation Treatment ◽

Dose Radiation

There is considerable evidence from experimental studies in animals, as well as from clinical reports, that low-dose radiation hormesis is effective for the treatment of cancer and ulcerative colitis. In this study, we present 3 case reports that support the clinical efficacy of low-dose radiation hormesis in patients with these diseases. First, a patient with prostate cancer who had undergone surgical resection showed a subsequent increase in prostate-specific antigen (PSA). His PSA value started decreasing immediately after the start of repeated low-dose X-ray irradiation treatment and remained low thereafter. Second, a patient with prostate cancer with bone metastasis was treated with repeated low-dose X-ray irradiation. His PSA level decreased to nearly normal within 3 months after starting the treatment and remained at the low level after the end of hormesis treatment. His bone metastasis almost completely disappeared. Third, a patient with ulcerative colitis showed a slow initial response to repeated low-dose irradiation treatment using various modalities, including drinking radon-containing water, but within 8 months, his swelling and bleeding had completely disappeared. After 1 year, the number of bowel movements had become normal. Interest in the use of radiation hormesis in clinical practice is increasing, and we hope that these case reports will encourage further clinical investigations.

Download Full-text