Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are ...less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.
Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved ...cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2‐LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient‐derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.
What's new?
Clinical trials of osteosarcoma therapies are difficult to conduct given the low incidence of the disease. While in vitro studies have identified histone deacetylase (HDAC) inhibitors as a potential treatment, their efficacy in vivo largely remains untested. This study found that the broad‐spectrum HDAC inhibitor panobinostat blocks spontaneous osteosarcoma metastasis to the lung when used as a single agent. Panobinostat also impaired growth of established lung metastases and improved overall survival. Mechanistically, HDAC1/2 emerged as important drivers of osteosarcoma growth and metastasis. Altogether, the findings provide a strong rationale for the design of clinical trials to test panobinostat in humans.
Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of ...cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.
Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases (RTKs). Although most ...GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly platelet-derived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.
Abstract Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular mass hyaluronic acid, a major non-protein component of ...extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. Here we investigated the potential of targeting hyaluronidases to reduce metastasis. A high throughput screen identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and reduced migration and invasion behavior of breast, prostate, and melanoma cancer cells. Moreover, delphinidin treatment suppressed melanoma metastasis in mice. Our study provides a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. Furthermore, we identified a natural compound delphinidin as a potential anticancer therapeutic. Thus, we have identified a path for clinical translation of the cancer resistance mechanism identified in the naked mole rat.
Bone metastatic prostate cancer provokes extensive osteogenesis by driving the recruitment and osteoblastic differentiation of mesenchymal stromal cells (MSCs). The resulting lesions greatly ...contribute to patient morbidity and mortality, underscoring the need for defining how prostate metastases subvert the MSC-osteoblast differentiation program. To gain insights into this process we profiled the effects of co-culture of primary MSCs with validated bone metastatic prostate cancer cell line models. These analyses revealed a cast of shared differentially induced genes in MSC, including betaglycan, a co-receptor for TGFβ. Betaglycan has not been studied in the context of bone metastatic disease previously. Here we report that loss of betaglycan in MSC is sufficient to augment TGFβ signaling, proliferation and migration, and completely blocks the MSC-osteoblast differentiation program. Further, betaglycan was revealed as necessary for prostate cancer-induced osteogenesis in vivo. Mechanistically, gene expression analysis revealed betaglycan controls the expression of a large repertoire of genes in MSCs, and that betaglycan loss provokes >60-fold increase in the expression of Wnt5a that plays important roles in stemness. In accord with the increased Wnt5a levels, there was a marked induction of canonical Wnt signaling in betaglycan ablated MSCs, and the addition of recombinant Wnt5a to MSCs was sufficient to impair osteogenic differentiation. Finally, the addition of Wnt5a neutralizing antibody was sufficient to induce the expression of osteogenic genes in betaglycan-ablated MSCs. Collectively, these findings suggest a betaglycan-Wnt5a circuit represents an attractive vulnerability to ameliorate prostate cancer-induced osteogenesis.
Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release ...of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138
myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent
studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed.
stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the
efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.
Abstract
Prostate cancer frequently metastasizes to bone, resulting in increased risk of fractures and severe pain that significantly impacts patient quality of life. Bone metastatic prostate cancer ...is currently incurable with standard of care therapies being mainly palliative. In bone, prostate cancer generates extensive osteogenic lesions by promoting osteoblast activity. Osteoblasts are specialized bone forming cells derived from mesenchymal stem cells. In a bid to find new molecular targets through which prostate cancer induces osteogenesis, we incubated naïve MSCs with osteogenic bone metastatic prostate cancer cell line C4-2B conditioned media. Gene expression analysis revealed a 3-fold increase in expression of the TGFâ co-receptor, betaglycan. Given the critical role of TGFâ in the context of bone metastatic disease, we examined the role of betaglycan in MSC behavior. To this end, we utilized shRNA to knockdown betaglycan gene expression in mouse bone marrow-derived primary MSCs. Reduced betaglycan expression in knockdown (KD) MSCs had little to no impact on the expression of TGFâ signaling receptors, TGFâRI and TGFâRII, or pan-TGFâ ligand expression. However, using PAI promoter activity, a readout for TGFâ signaling, we observed a 3-fold increase in luminescence in KD-MSCs compared to controls. Likewise, phosphorylated Smad 2 was significantly increased in Betaglycan KD-MSCs in response to TGFâ treatment, collectively demonstrating increased TGFâ signaling in MSCs with reduced betaglycan expression. Using modified Boyden chamber assays, we found that 50% more Betaglycan-KD MSCs migrated towards recombinant TGFâ than controls (100 KD-MSCs cells migrated towards recombinant TGFâ vs. 50 control cells); this change was reversed with the addition of recombinant betaglycan. Using osteogenic differentiation assay, we found that Betaglycan KD-MSC differentiation was reduced by approximately 70% compared to control MSCs as measured by alizarin red staining. Addition of recombinant TGFâ further suppressed differentiation in both KD-MSCs and Control MSCs. This phenomenon was rescued by the addition of recombinant betaglycan, suggesting that MSC-derived betaglycan is critical for driving the osteogenic program. We are currently determining the impact of betaglycan on MSC behavior in the tumor bone microenvironment using in vivo models of bone metastatic prostate cancer. Collectively, these findings suggest that prostate cancer-induced MSC osteogenic programs are regulated in part via the induction of betaglycan.
Citation Format: Leah M. Cook, Jeremy J. McGuire, Conor C. Lynch. Betaglycan-mediated regulation of mesenchymal stromal cell behavior in the prostate tumor-bone microenvironment. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 749.
e24076 Background: Manypatients with cancer receiving hormone therapy experience difficulty with sleeping and insomnia. Reiki is a technique where therapy is delivered to the patient with either no ...or very light physical touch whereas traditional massage therapy uses pressure and movement by the therapist to manipulate soft tissue. Both Reiki and traditional massage therapy have been shown by others to be effective in providing benefits in sleep quality. This study is the first to compare changes in sleep quality after massage and Reiki treatments in patients with prostate and breast cancer receiving hormone therapy. Methods: Eighty-seven, breast (n = 56) and prostate cancer (n = 31), patients receiving hormone therapy experiencing self-reported fatigue ≥4/10were included in this randomized controlled trial (RCT). Patients were randomized into one of three treatment arms for 4-weeks: Arm 1 received two massage treatments, Arm 2 received two Reiki treatments and Arm 3 received four Reiki treatments. Each treatment session was approximately 75 minutes. . Participants with a baseline score of ( ≥8) on the ISI were included in this analysis. Results: 75% of all enrolled participants (n = 65) met the inclusion criteria for baseline clinically meaningful insomnia. Both Reiki and massage provided improvement in sleep quality from pre to post intervention and there was no difference between 2 and 4 Reiki sessions. Reiki significantly increased sleep quality (p > .01) with a mean decrease in total ISI score of 2.96. Massage therapy showed a trend towards improved sleep quality (p = 0.06) with a mean decrease in ISI score of 1.95. There was a clinically meaningful decrease in total ISI score (≥6) in 15% of those who received massage therapy compared to 25% in the reiki therapy group. Conclusions: Four weeks of Reiki significantly improved sleep quality in patients with breast and prostate cancer receiving hormone therapy. Reiki may be a better non-pharmacologic therapeutic for improving sleep quality. Clinical trial information: NCT02758756 .
e24160
Background: Disease-specific quality of life (QOL) is consistently regarded as one of the most important outcomes by women with metastatic breast cancer (mBC), and it predicts survival. ...Treatment-related symptoms such as cognitive impairment greatly impact QOL in women with mBC. Patients undergoing treatment for breast cancer are highly interested in diet and nutrition, but despite this high level of interest, very few trials have tested dietary interventions in women receiving systemic breast cancer therapy and; the majority of research has been conducted in survivors who have completed primary treatment. Given the limited treatment options for cognitive impairment we evaluated whether our results show a whole food plant based (WFPB) dietary intervention might improve perceived cognitive function (CF) in women undergoing treatment for metastatic breast cancer. Methods: Patients with stage 4 breast cancer receiving treatment were randomized 2:1 into 2 arms: 1) WFPB diet (n = 20) or 2) usual care (n = 10) for 8 weeks with assessments at baseline, and 8 weeks. Our WFPB diet consisted of an ad libitum whole-food, plant-based diet; 3 meals/day were provided, which included fruits, vegetables, whole grains, nuts/seeds and excluded meat, dairy, eggs, added oils, solid fats and most sugars. Patient reported outcomes for perceived CF were collected using FACT- COG and EORTC-QLQ-C30. Paired t-tests were used to assess within group changes from baseline to week 8. The between group difference (WFPB diet vs control) was assessed by ANCOVA model. Results: Patients on the WFPB diet began with a mean baseline score of 140.8 on the FACT-COG which significantly improved to 156.6 (p = 0.005) at 8-weeks post intervention. The reported minimally important difference (MID) between groups is (9.6) and we observed a clinically significant difference of 17.1 (p = 0.03). Similar results in CF were observed for EORTC-QLQ-C30. The baseline mean score of 73.3 was improved to 84.7 (p = 0.004) at 8-weeks post intervention. The reported MID between groups is (4) and we observed a clinically significant difference of 12.6 (p = 0.07), with no significant changes in perceived CF for the control group. Conclusions: Our 8-week WFPB diet resulted in clinically meaningful and statistically significant improvements in perceived cognitive function in women with metastatic breast cancer. A phase 3 clinical trial is needed to confirm the results of this novel intervention. Funding: 3UG1CA189961. Clinical trial information: NCT03045289 .Table: see text
PDF
