Dr. Weeks’ Comment: Roll up your sleeves and study this newly published article in Nature on how prostate cancer spreads. These researchers explore the genetic predispositions which set the stage for cancer either spreading or not. What they don’t say, (which could save your life) is that the behavior (expression) of the “dangerous” microRNA and genes (miR-15, miR-16, BCL2, CCND1, CCNE1 and CDK4-6, BMI-1, EMT AP4, FGF-2, FGFR1, miR-21, and TGF-β) are under the control of the epigenetic environment in general and the degree of inflammation in particular. If a patient had all the potentially dangerous miRNA signatures, the wise doctor would simply recommend that the patients just feed those genes wisely with anti-inflammatory diet in general and with whole, crushed, organic non-GMO black cumin and black raspberry and Chatrdionnay grape seeds in particular. Remember, while genetics is the focus of most cancer research funding, epigenetics cause the great majority of cancers! A wise doctor once told me “Remember Brad, Genetics loads the gun, but epigenetic factors pull the trigger.” Feed your genes wisely to optimize their performance.
A microRNA code for prostate cancer metastasis
OPEN
D Bonci1,2, et al 1Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità , Rome, Italy
Advance online publication 15 June 2015
Abstract
Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-β and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients’ cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.
Introduction
Skeletal metastases occur in more than 80% of cases of advanced-stage prostate cancer and are a major detrimental event for patients.1 Tumor cell homing into the bone marrow promotes dramatic alterations in osteoblast and osteoclast function and bone remodeling, causing severe lesions. Metastatic prostate cancer cells acquire a bone cell-like phenotype by a process, called osteomimicry, which allows their survival and proliferation in the bone marrow microenvironment. At the same time, osteoblasts and osteoclasts aberrantly modify their proliferation and differentiation programs during the metastatic process, thereby altering bone density.2, 3, 4 Although the different steps that characterize the development of prostate cancer metastases have been essentially defined, the molecular events that trigger and fuel the bone colonization and metastatic progression are still unknown.
Development of metastasis requires migratory and invasive capacity of tumor propagating cells to distant sites. Migration and invasion are features shared by undifferentiated tumor cells showing traits of epithelial-mesenchymal transition (EMT), a process driven by genetic and epigenetic signals greatly influenced by the tumor microenvironment. In the bone marrow microenvironment, stromal and metastatic prostate cancer cells produce TGF-β,5 which is released in sera of advanced patients.6 The ability of TGF-β inhibitors to prevent the formation of bone metastasis in preclinical models suggests that TGF-β may have a considerable role in prostate cancer progression.7 Aberrant TGF-β signaling can promote the expansion of tumor propagating cells and the conversion of early epithelial tumors to invasive and metastatic cancers through the induction of EMT.8 Another relevant pathway in prostate cancer may be represented by Hh signaling. Initial studies have shown that Hh targeting suppresses the growth of prostate cancer cell lines and displays therapeutic activity in prostate cancer xenografts.9, 10 More recent data indicate that IHH promotes the expansion of tumor propagating cells through the direct transcriptional control of the polycomb gene Bmi-1,11 which has a key role in prostate cancer initiation and progression.12
Compelling evidence demonstrates microRNAs (miRNAs) have a central role in controlling basic cell functions, including migration and invasion.13, 14 The expression of miRNAs is widely altered in cancer,15 suggesting that miRNA deregulations are deeply implicated in tumor development and progression.16, 17Several articles demonstrate that miR-15 and miR-16 (miR-15/16) deregulation is associated with cancer progression by targeting several oncogenes, such as BCL2, CCND1, CCNE1 and CDK4-6, which promote cell proliferation and survival,18, 19, 20, 21 induction of BMI-122 and EMT through the regulation of AP4.23 Moreover, other data suggest that miR-15 and miR-16 control the expression of FGF-2, FGFR1, VEGF and WNT signaling,24, 25 which are able to promote tumor angiogenesis and bone metastases.
miR-21 is one of the most commonly and highly upregulated oncomir in many types of cancer.26 In prostate cancer, miR-21 promotes hormone-dependent and hormone-independent growth.27 Importantly, RAS induces the upregulation of miR-2128 and significantly contribute to the aggressiveness of several tumor types.29Although not frequently mutated in prostate cancer, RAS isoforms have a pivotal role in multiple pathways that have been implicated in prostate tumorigenesis. Furthermore, RAS has been shown to promote prostate cancer progression by working synergistically with other pathways. In particular, a large body of literature indicates cooperation between RAS and TGF-β, including a prominent role of RAS signaling in the conversion from anti- to pro-oncogenic TGF-β signaling.30Interestingly, the TGF-β inhibitor SMAD7 has been described as a target of the RAS downstream effector miR-21.31.…….. We clarify how RAS, TGF-β and Hedgehog signaling cooperate in concert with miR deregulation to promote cancer progression and bone alteration in prostate cancer.
MiR-15 and MiR-16 Downregulation Promotes Tumor Growth and Invasion
Thus, miR-15/miR-16 control organ-confined and distant invasion of prostate cancer cells.
……. Thus, the considerable enhancement of TGF-β signaling induced by the modulation of miR-15/miR-16 and miR-21 promotes cancer progression and metastatic spreading.
In this study we explored the molecular events causing bone lesions in murine models obtained with progressively transformed prostate cells. We demonstrated that miR-21 upregulation and loss of miR-15/miR-16 cluster cooperate to promote bone colonization and damage through the potentiation of TGF-β signaling. Such miRNA deregulation in prostate cancer promotes a plethora of effects mediated by the altered expression of their multiple targets. Aberrant TGF-β signal cascade can synergize with RAS, WNT, Hedgehog signaling, androgen receptor, FGF-2/FGFR1 axis, AKT and EGFR signaling in the context of an extremely aggressive phenotype that promote bone lesions.
Loss of MiR-15/MiR-16 cluster and upregulation of MiR-21 are critical events in the development of prostate cancer metastasis
The main features of prostate cancer cells with loss of miR-15/miR-16 and upregulation of miR-21 are increased aggressiveness, dedifferentiation and acquisition of a strong EMT phenotype, indicating that these alterations synergistically cooperate to maximize the malignancy of prostate cancer cells.
…..Thus, the considerable enhancement of TGF-β signaling induced by the modulation of miR-15/miR-16 and miR-21 promotes a stem cell-like phenotype with features of EMT in prostate cancer cells and promotes cancer progression and metastatic spreading.
Clinical considerations and conclusions
Administration of targeted or conventional therapies requires accuracy of staging procedures and biomarkers predictive of patients’ response. Thus, although considerable efforts have been done in the attempt to identify patients at high risk of biochemical/radiological recurrence, currently available risk stratification models and predictive nomograms lack of the adequate accuracy. The proposed miRNA signature does not significantly correlate with higher Gleason scores or prostate specific antigen levels (data not shown), suggesting that this signature may add additional information over conventional analysis. The functional roles of miRNAs in tumor biology is deeply investigated and many evidences report that tissue or blood-based miRNA biomarkers that predict clinical behavior and/or therapeutic response can be used as prognostic and predictive biomarkers.64, 65 For the above reasons, our data suggest that miR-15 and miR-16 downregulation together with miR-21 upregulation should be investigated in order to verify whether these molecular parameters increase the accuracy of current predictors and, given the multiple molecular abnormalities related with their deregulation, as predictive biomarkers for optimal testing of innovative molecular targeted agents and bone-acting compounds. Furthermore, if validated in adequately powered clinical trials, our results can allow to optimize patients selection in clinical studies for bone metastasis prevention, which may envision the use of bone-acting agents in non-metastatic prostate cancer patients.66
Our results provide a rationale for biomarker-based bone metastasis prevention clinical trials, and define new ground for the development of novel therapies of advanced prostate cancer. Although our data may suggest new druggable pathways for bone metastases prevention and treatment, the therapeutic use of miRNA modulation in prostate cancer appears an extremely promising advancement toward more effective treatments.