New Italian paper below. [1]
Mark Moyad has been saying for many years that "Heart-healthy is prostate-healthy." It is known that men with PCa have a higher risk for cardiovascular-related mortality - even if not on ADT - and that men with PCa often exhibit symptoms of the metabolic syndrome [MetS], so Moyad's claim doesn't sound outlandish to me.
And, of course, Dr. Myers promoted the Mediterranean diet - the full 40% fat diet - & said that the PREDIMED trial convincingly showed that the Med diet could improve cardiovascular health. Myers noted that his patients on low-fat diets didn't do well.
Myers even wrote about the Med diet in his: "New Prostate Cancer Nutrition Book"
The new paper is titled: "Mediterranean Diet Food Components as Possible Adjuvant Therapies to Counteract Breast and Prostate Cancer Progression to Bone Metastasis".
From Section 4: (TMI for some, but worth a look. You will notice many of the biochemicals that I have written about, that are available in supplement form in the U.S. But food sources are good too. LOL)
4.1. Nutrients in the Epithelial-Mesenchymal Plasticity
Many data have been collected regarding the ability of compounds mostly belonging to vegetables and fruits present in the MD to interfere with the phenotypic plasticity and invasiveness of different types of malignant cells, as asserted by in vitro studies, even if the mechanisms of action have not always been defined. Some of these compounds owe their anti-metastatic effectiveness to their ability to interfere with the EMT, downregulate the expression of MMPs, and act by modifying the behavior of signaling proteins. Concerning breast cancer, the most commonly used cellular system employs the triple negative and highly invasive MDA-MB-231 cells exposed to natural compounds.
It was reported that both polyphenols and non-phenolic nutrients are able to exert anti-invasive activity in vitro in many cell types, among the ones in breast cancer cells. Resveratrol has shown the ability to upregulate E-cadherin and downregulate mesenchymal markers in several cell types, including breast cancer cells, multiple myeloma cell lines, and colorectal cancer cells [61,62,63]. Resveratrol in breast cancer cells appears to increase E-cadherin expression through the inhibition of TGF-β1-induced EMT, by regulating Smad-dependent and Smad-independent pathways [59].
Resveratrol also prevents prostate cancer invasion and metastasis through several mechanisms: by reverting the EMT process, downregulating the androgen receptor and CXCR4 (CXCL12 chemokine receptor 4) pathway [64], by intervening in the bi-directional interplay between stromal and epithelial cells, and by inhibiting HGF-induced migratory behavior of prostate cancer cells [65]. Therefore, all these data reveal how resveratrol can intervene in the regulation of the metastatic phenotype of both breast and prostate cancer cells through multiple mechanisms.
Li et al. suggested that in prostate cancer cells, resveratrol can inhibit the EMT process (LPS induced, used to trigger EMT in PC-3 cells) probably through the inhibition of Hedgehog signaling, one of the pathways that regulates EMT in tumor growth [66].
S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) present in garlic have shown the ability to restore E-cadherin expression in addition to inhibiting cancer cell proliferation in androgen-independent prostate cancer cells. The restoration of E-cadherin expression seems to be due to the contemporary transcriptional activation of the E-cadherin gene and the decreased expression of the Snail gene, an E-cadherin suppressor [67]. Another allium derivative, diallyl disulfide (DADS), has been demonstrated to both decrease the expression and protein synthesis and inhibit the activity of MMP-2 and -9 in human prostate carcinoma LNCaP cells [68]. In MDA-MB-231 breast cancer cells, DADS, besides similar effects on MMP-9, showed other abilities: inhibition of cell migration and invasion, reversion of EMT, and finally induction of apoptosis through the modulation of the β-catenin signaling pathway [69].
The tyrosol derivatives (-)-oleocanthal in extra virgin olive oil are recognized to act in more than one way in the modulation of the phenotype plasticity of mammary cancer cells: (i) suppressing the expression of the mesenchymal marker vimentin; (ii) restoring the expression of E-cadherin and Zo-1 in MDA-MB-231 cancer cells; (iii) stabilizing the expression of E-cadherin and Zo-1 in MCF-7 and BT-474 breast cancer cells; (iv) blocking the HGF/c-Met activation in MDA-MB-231, MCF-7, and BT474 cancer cell lines in culture [70,71].
Kaempferol, a phytoestrogen present in fruits and vegetables, is considered as a promising therapeutic agent for cancer metastasis for its action against adhesion, migration, and invasion of MDA-MB-231 human breast carcinoma cells [72]. In addition, kaempferol can reduce both the activity and expression of MMP-2, MMP-9, and cathepsin in MCF-7 breast cancer cell lines [72,73]. Moreover, in triple-negative breast cancer cells (TNBCs), low doses of kaempferol can downregulate RhoA and Rac1 signaling pathways. In ER-positive breast cancer cells (MCF-7), kaempferol, through the regulation of protein expression involved in EMT as well as the metastasis-related genes, suppresses E2 (17-β-estradiol) or triclosan-induced EMT, migration, and invasion [73,74]. Therefore, kaempferol could be considered as a potent chemopreventive compound against breast cancer metastasis, to be used alternatively to hormone replacement therapy.
Indole-3-carbinol (I3C) and indole[3,2-b] carbazole (ICZ) from cruciferous vegetables have shown the ability to inhibit breast cancer cell migration by multiple activities. First, in MCF-7 breast cancer cells treated with I3C and ICZ, E-cadherin mRNA expression was increased while vimentin mRNA expression was attenuated. Second, the MMP-2 and -9 activity as well as the focal adhesion kinase (FAK) mRNA expression were decreased, thus demonstrating an inhibition of the EMT process [75].
Crocin and crocetin, two saffron carotenoids, have displayed the ability to inhibit murine metastatic breast cancer cell (4T1) migration and invasion in addition to attenuating the adhesion to extracellular matrix in vitro. The mechanism affected seems to be related to the Wnt/β-catenin pathway [76].
Soy isoflavones are highly involved in the progression to bone metastasis of prostate cancer at different levels. The first level is the reversion of the EMT process. Low doses of genistein (4′,5,7-trihydroxyisoflavone) for 48 h are able to reverse the EMT process in prostate cancer cell lines LNCaP, LNCaP/HIF-1a, and IA8-ARCaP, as demonstrated by the cell morphological features and the upregulation of the E-cadherin together with the loss of expression of vimentin [77]. Genistein can also inhibit MMP-2 expression in both PC3 and LNCaP cells in a dose- and time-dependent manner [78]. In addition, genistein is able to diminish the expression of several MMP genes, especially of MMP-9, both in vitro (PC3 cells) and in vivo (PC3 bone metastasis xenograft model), presumably by inhibiting the NF-κB DNA-binding activity [79] involved in MMP gene expression [80].
Anthocyanin 3,5-diglucoside, the major phytochemical constituent of muscadine grape skin extract, due to its antioxidant potential, facilitated the MET process in prostate cancer cells characterized by re-expression of E-cadherin and reduced vimentin levels. This effect is due to the antagonization of the action of Snail, a key player of EMT, caused by the inhibition of the JAK/STAT pathway [81]. Since Snail overexpression increased cathepsin L activity via STAT3 signaling, useful for migration, invasion, and osteoclastogenesis, the muscadine grape skin extract, due to its content of anthocyanin, ellagic acid, and ellagic acid precursor, could be of interest as a therapeutic agent in breast and prostate bone metastasis [82].
Silibinin, a flavanone isolated from milk thistle, decreased vimentin protein expression in a dose- and time-dependent manner and suppressed MMP-2 expression, while it regulated cytokeratin-18 gene in ARCaPM cells, an in vitro model of prostate cancer progression to bone metastasis [83]. The possible mechanism seems to be related to the downregulation of Slug and ZEB1, EMT regulators [84].
Curcumin, one of three major curcuminoids derived from turmeric, is well known for a plethora of activities against tumor cells. As it regards the present issue, curcumin has shown the ability to (i) inhibit proliferation and colony formation of breast cancer cell lines, MCF-7 and MDA-MB-231; (ii) suppress the migration and invasion of MDA-MB-231 cells; (iii) downregulate the mRNA expression of vimentin, fibronectin, and β-catenin; (iv) upregulate the mRNA expression of E-cadherin. Together, these activities indicate the possibility to counteract the EMT process in breast tumors [85].
Ferulic acid, a polyphenol contained in numerous plants, can inhibit migration and revert EMT in vitro in MDA-MB-231 cells. This effect was also confirmed in vivo in the xenograft model of breast cancer [86].
4.2. Nutrients in the Osteolytic Bone Metastasis
The combined effect of dietary grape polyphenols (5 mg/kg each of resveratrol, quercetin, and catechin) was tested on the progression of mammary tumors in the highly metastatic ER (-) MDA-MB-435 cell line. Molecular analysis of excised tumors demonstrated that the treatment reduces tumor growth due to upregulation of forkhead box O1 (FOXO1) and NFKBIA (IκBα), thus activating apoptosis and potentially inhibiting NF-κB activity. The image analysis of distant metastases demonstrated that grape polyphenols reduce metastasis, especially to liver and bone [87]. Some turmeric extracts with a precise content of phenolic compounds have been demonstrated to inhibit MDA-MB-231 cell growth and the secretion of PTHrP that drives breast cancer bone metastases in advanced disease as an osteolytic factor [88,89]. In in vitro experiments using MDA-MB-231 cells, curcumin also revealed the ability to block Smad-dependent TGF-β signaling, which is supposed to induce PTHrP release [90] and the progression to bone metastasis in vivo [88]. Interestingly, successive experiments have demonstrated that curcumin-glucuronide is the prevalent circulating form and that bone marrow cells can carry out curcumin deglucuronidation. This ability at the bone level is of fundamental importance since the released curcumin is able to reduce the receptor-mediated phosphorylation of Smad2 [89]. Curcumin can also suppress RANKL-induced osteoclastogenesis induced by prostate cancer cells [91].
Green tea (Camellia sinensis) extract containing the polyphenols epicatechin (EC), EC gallate (ECG), epigallocatechin (EGC), and EGC gallate (EGCG) has demonstrated anti-metastatic and anti-osteolytic effects in in vitro and in vivo experiments using 4T1 cells, a mouse mammary tumor cell, and in a mouse mammary tumor model obtained by inoculating 4T1 cells at the subcutaneous level. The activities exerted by the extract are (i) the dose- and time-dependent inhibition of in vitro cell viability; (ii) the increase in the expression of the pro-apoptotic protein Bax; (iii) the decrease in the expression of the anti-apoptotic protein Bcl-2; (iv) the inhibition of the migration and invasion of 4T1 cells; (v) the decrease in the number of in vitro osteoclasts together with a decrease in osteolysis in vivo; (vi) an increase in the bone volume [92].
Sulforaphane is a phytochemical from cruciferous vegetables with known anti-cancer properties. As concerns the present issue, the main positive effect of sulforaphane treatment is the enrolment of a new gene network, i.e., RUNX2, NF-κB1, and SOX9, which becomes downregulated, and in turn negatively affects the transcription and secretion of collagen type 1 α1 (COL1A1), a metastasis-promoting factor, MMP-9, and cathepsin K (CTSK), matrix-degrading factors involved in breast cancer metastasis. In addition, sulforaphane inhibits osteoclast differentiation [93].
In a xenograft model of bone metastasis, Pore et al. demonstrated that the oral administration of sulforaphane reduced breast cancer-induced osteolytic bone metastasis via a significant decrease in circulating IL-8 [93].
N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) contained in fish oil have been shown to prevent the formation of osteolytic lesions by targeting the pro-metastatic protein CD44, implying the suppression of metastases to the bone. In a model of bone metastasis of breast cancer, it was argued that fish oil is an important dietary supplement to consider in adjuvant therapy for bone metastases [94].
Other authors have reported that DHA attenuates breast cancer bone metastasis and associated osteolysis more potently than EPA, possibly by inhibiting migration of breast cancer cells to the bone as well as by inhibiting osteoclastic bone resorption [95].
It is worth remembering that bone loss due to the combined mechanisms of osteoclast activation and estrogen depletion can also occur during aromatase inhibitor therapy for breast cancer with a consequent increase in fracture rate and osteoporosis. Although not directly related to bone metastasis, the positive effects of vitamin D [96], EPA, and DHA supplementation [97] in reducing bone loss in these patients deserve to be considered.
Trolox, a vitamin E analog, has been shown to inhibit breast cancer-induced bone destruction when administered to mice before the injection of 4T1 breast cancer cells in an experimental model of osteolytic metastasis. The authors claim that trolox exerts anti-metastatic and anti-osteolytic activities in breast cancer cells through Prostaglandin E2 (PGE2)-dependent and PGE2-independent mechanisms [98].
Glycitein, a phytoestrogen belonging to the group of isoflavones, increased osteoclast apoptosis and decreased the mRNA expression of RANKL, without affecting OPG, in a murine in vitro model. Moreover, glycitein decreased IL-6 mRNA expression in osteoblasts. IL-6, a well-known pro-inflammatory cytokine, is involved in bone resorption and in osteoclast formation and thus the interesting role exerted by glycitein on IL-6 should be analyzed in more detail [99].
Dietary genistein was able to upregulate the expression of OPG in PC3 bone tumors, leading to a possible inhibitory effect on osteoclast formation [80]. Subsequent studies have reported that daidzein and genistein increased PTHrP and PTH type 1 receptor (PTH1R) expression in human PCa cell lines in addition to the OPG/RANKL protein ratio [100].
More recently, a supposed synergistic action by daidzein and genistein in a soybean extract was able to stimulate the secretion of OPG and inhibit that of RANKL, a critical transcription factor for osteoclast differentiation, in osteoblasts, thus producing an indirect but useful inhibition of osteoclast differentiation [101].
Although the exact mechanisms are not fully elucidated, it was reported that in a murine model of bone metastasis, the vitamin D deficiency can affect the vicious cycle, resulting in increased growth of breast cancer cells in the bone environment, accompanied by osteolytic lesions [102].
Resveratrol upregulates protein and mRNA expression of major histocompatibility complex class I chain-related proteins A and B (MICA and MICB) in breast cancer cells, which in turn promote breast cancer cell lysis by natural killer (NK) cells in vitro and in vivo. In this way, resveratrol could both counteract the immune escape and improve the immunogenicity of cancer cells [103].
4.3. Nutrients in Osteoblastic Bone Metastasis
Genistein and soy isolate have demonstrated the ability to induce a possible decrease in Wnt/β-catenin expression and protein levels, respectively, by modulating GSK-3 activity through the frizzled 3 receptor, resulting in increased degradation of β-catenin and cell growth [13].
The flavonoid p-hydroxycinnamic acid (HCA) has demonstrated prevention activity toward suppressed osteoblastogenesis and enhanced osteoclastogenesis in MDA-MB-231 cells co-cultured with bone marrow cells. The supposed mechanism is the antagonization of the activation of NF-κB signaling induced by RANKL [104].
As concerns bone colonization by prostate cancer, curcumin has demonstrated multiple activities: it downregulates the expression of CXCR4, the receptor of the stromal chemokine CXCL12 expressed by osteoblasts and involved in the metastatic process [105]; it inhibits the serine/threonine kinase Akt activation and suppresses cell proliferation [106]. Moreover, curcumin can block the chemotactic effects of CC motif ligand 2 (CCL2) on invasion, adhesion, and motility of PCa cells; the effect is partially due to a differential regulation of PKC and MMP-9 signaling [107]. Dorai et al. analyzed the possibility of using curcumin as a therapeutic agent in advanced prostate cancer, particularly concerning skeletal complications. Curcumin seems to modulate TGF-β (that plays a central role in the vicious cycle of bone metastasis) through the antagonistic action exerted by BMP-7 in both osteolytic and osteoblastic metastasis from prostate cancer. Thus, curcumin is able (either directly in cancer cells or indirectly in bone marrow-derived stem cells) to reprogram the check and balance of TGF-β signaling pathways by the upregulation of the expression of BMP-7. Using an animal model of bone metastasis, the authors argued the importance of using curcumin as a dietary ingredient to prevent bone metastasis [108].
It has been reported that dietary intake of ω-3 PUFAs decreases the risk of developing aggressive/metastatic prostate carcinoma [109]. Brown and colleagues reported that high ω-3: ω-6 PUFA ratios together with a large amount of eicosapentaenoic acid (EPA) in the diet can counteract the metastatic process to bone through the blocking of PGE2 production, leading to a reduced risk of aggressive disease [110].
In Figure 2, bioactive molecules in the MD are reported according to their role in the development of osteoblastic metastasis.
4.4. Nutrients with an Assessed Anti-Bone Metastatic Role although Not Specifically Related to Breast/Prostate Cancer or to the Mechanisms Described Above
There are a plenty of studies highlighting the ability of different natural compounds, mainly present in vegetables, to inhibit or counteract the formation and progression of bone metastasis. Although these studies are not directly related to breast/prostate cancer, it is of interest to consider them in the perspective that some of these compounds and activities could in the future also be associated with prostate/breast cancer and bone metastasis.
Dietary N-(4-hydroxyphenyl) retinamide (4-HPR), a synthetic amide of retinoic acid, has demonstrated anti-metastatic effects in the highly aggressive in vivo mouse prostate reconstitution (MPR) model in which either heterozygote or homozygote p53-deficient fetal prostate is initiated with ras and myc oncogenes. Multiple pathways associated with cell apoptosis and/or G1 arrest seem to be involved in the 4-HPR activity [111].
The activation of silent information regulator 7 (SIRT7) deacetylase by resveratrol inhibits breast cancer lung metastasis by antagonizing TGF-β1 signaling [12].
The flavonoid apigenin (API),4′,5,7-trihydroxyflavone can suppress the oncogene Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) expression normally upregulated in prostate cancer and responsible for the invasion and metastasis of cancer cells in a human prostate cancer xenograft model. The exact mechanism used by API consists in targeting the Snail/Slug-mediated EMT process [112]. In addition, API can suppress the signaling pathway due to IL-6 which is responsible for chronic inflammation associated with breast cancer, for instance, and responsible for the EMT process, the invasion and migration of tumor cells [113].
-Patrick
Diet in the prevention of cancer and ancer metastasis
