Dynamic modeling of bone remodeling, osteolytic metastasis and PK/PD therapy: introducing variable order derivatives as a simplification technique.

Bone is constantly being renewed: in the adult skeleton, bone resorption and formation are in a tightly coupled balance, allowing for a constant bone density to be maintained. Yet this micro-environment provides the necessary conditions for the growth and proliferation of tumor cells, and thus bone is a common site for the development of metastases, mainly from primary breast and prostate cancer. Mathematical and computational models with differential equations can replicate this bone remodeling process. These models have been extended to include the effects of disruptive tumor pathologies in the bone dynamics, as metastases contribute to the decoupling between bone resorption and formation and to the self-perpetuating tumor growth cycle. Such models may also contemplate the counteraction effects of currently used therapies, and, in the case of treatments with drugs, their pharmocokinetics and pharmacodynamics. We present a thorough overview of biochemical models for bone remodeling, in the presence of a tumour together with anti-cancer and anti-resorptive therapy, formulated as systems of first-order differential equations, or simplified using variable order derivatives. The latter models, of which some are new to this paper, result in equations with fewer parameters, and allow accounting for anomalous diffusion processes. In this way, more compact and parsimonious models, that promptly highlight tumorous bone interactions, are achieved, providing an effective framework to counteract the loss of bone integrity on the affected areas.

Effect of biologic disease-modifying anti-rheumatic drugs targeting remission in axial spondyloarthritis: systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy of biologic DMARDs (bDMARDs) in achieving Assessment of Spondyloarthritis International Society partial remission (ASAS-PR) and/or Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS-ID), as remission-like surrogates, in axial SpA (axSpA). METHODS: Data from randomized controlled trials (RCTs), including long-term extensions, were included. A systematic literature review was performed using the MEDLINE database (first search May 2018, updated February 2020) and PICO criteria according to Patients-adults with radiographic or non-radiographic axSpA; Intervention-any bDMARD; Comparator-placebo and/or any different drug; Outcomes-ASAS-PR and/or ASDAS-ID as primary or secondary endpoints. Meta-analysis was performed after assessment of the homogeneity of study designs, populations and outcomes. RESULTS: After screening 155 references, a total of 22 RCTs and 28 long-term extensions were retrieved. ASAS-PR was the dominant remission-like definition used. Concerning TNF inhibitors, 14/17 RCTs provided evidence of efficacy in reaching remission at different time points: 12, 16, 24 and 28 weeks (ASAS-PR in 16-62% of patients and ASDAS-ID in 24-40% of patients). With a limited number of studies available, IL-17A inhibitors exhibited remission rates of 15-21% for ASAS-PR and 11-16% for ASDAS-ID at week 16. A meta-analysis regarding ASAS-PR was performed considering RCTs with a similar duration (12, 16 or 24 weeks). The relative risk for achieving remission was 3.864 (95% CI 2.937, 5.085). CONCLUSION: bDMARDs have a clear impact in axSpA remission evaluated by ASAS-PR. Nevertheless, these data show an unmet need for improved reporting of remission-like outcomes.

Interaction between HFE and haptoglobin polymorphisms and its relation with plasma glutathione levels in obese children.

Obesity among children has emerged as a serious public health problem. The growing prevalence of childhood obesity has led to the appearance of serious complications, including a chronic systemic inflammation associated with oxidative stress.  In the present study, we analysed the interaction between two genes related with iron metabolism - HFE and haptoglobin - and the plasmatic concentration of glutathione, as a way to evaluate the antioxidant response capacity in obesity. To achieve this, 118 obese children and 89 eutrophic children were recruited for the study. Results showed that although obese children present a significantly decreased tGSH levels, once we analysed separately children based on their haptoglobin phenotype, the decreased tGSH levels is significant only for the Hp 2 allele. Additionally, Hp 2.2 obese children carrying H63D polymorphism show significantly lower tGSH/GSSG values. Our results found an association of haptoglobin and HFE with oxidative stress in childhood obesity.

Modelling cancer outcomes of bone metastatic patients: combining survival data with N-Telopeptide of type I collagen (NTX) dynamics through joint models.

BACKGROUND: Joint models (JM) have emerged as a promising statistical framework to concurrently analyse survival data and multiple longitudinal responses. This is particularly relevant in clinical studies where the goal is to estimate the association between time-to-event data and the biomarkers evolution. In the context of oncological data, JM can indeed provide interesting prognostic markers for the event under study and thus support clinical decisions and treatment choices. However, several problems arise when dealing with this type of data, such as the high-dimensionality of the covariates space, the lack of knowledge about the function structure of the time series and the presence of missing data, facts that may hamper the accurate estimation of the JM. METHODS: We propose to apply JM for the analysis of bone metastatic patients and infer the association of their survival with several covariates, in particular the N-Telopeptide of Type I Collagen (NTX) dynamics. This biomarker has been identified as a relevant prognostic factor in patients with metastatic cancer, but only using static information in some specific time points. RESULTS: We extended this analysis using the full NTX time series for a larger cohort of patients with bone metastasis, and compared the results obtained by the JM and the extended Cox regression model. Imputation based on fuzzy clustering was used to deal with missing values and several functions for NTX evolution were compared, such as rational, exponential and cubic splines. CONCLUSIONS: The JM obtained confirm the association between NTX values and patients' response, attesting the importance of this time series, and additionally provide a deep understanding of the key survival covariates.

Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases.

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis.

N-Telopeptide of Type I Collagen Long-Term Dynamics in Breast Cancer Patients With Bone Metastases: Clinical Outcomes and Influence of Extraskeletal Metastases.

BACKGROUND: Markers of bone metabolism, such as N-telopeptide of type I collagen (NTX), have been demonstrated to be prognostic in previous trials of breast cancer (BC) patients with bone metastases (BMs). In the present study, we tested the survival effect of the NTX response to zoledronic acid (ZA) at 3 and 12 months in a contemporaneous cohort of BC patients with BMs and evaluated the influence of extraskeletal metastatic disease on NTX variation. PATIENTS AND METHODS: The present study was a prospective cohort study of consecutive BC patients diagnosed and treated at a single center. Patients presenting with de novo radiological evidence of BMs who started monthly intravenous ZA were included. Urinary NTX was measured at baseline and 1, 3, 6, 9, and 12 months after ZA introduction. RESULTS: Overall, 71 patients were enrolled, 32 with BMs and 39 with BMs plus extraskeletal metastases. The proportion of patients with elevated NTX at baseline and 3 and 12 months was 49.3%, 26.6%, and 34.2%, respectively. The variables associated with survival included age at diagnosis, tumor estrogen receptor status, and NTX at 3 and 12 months. Multivariate analysis showed that, in addition to age at diagnosis, only the 3-month NTX level was significantly associated with survival. Patients with BMs plus extraskeletal metastases had an erratic NTX variation pattern, unrelated to survival. CONCLUSION: In the present contemporaneous cohort of BC patients with BMs, the NTX response at 3 months was strongly associated with survival. Furthermore, an early response to ZA was strongly associated with long-term NTX control. Finally, patients with BMs plus extraskeletal metastases had an erratic NTX variation. IMPLICATIONS FOR PRACTICE: The present study showed that when accommodating recent therapy innovations and longer patient survival, the N-telopeptide (NTX) variation at 3 months is strongly associated with survival. In this setting, in addition to a few other clinicopathological features, NTX is a powerful prognostic marker. Moreover, early NTX correction associates with persistently normal NTX. This might identify a subgroup of patients with a good prognosis who are eligible for premature zoledronic acid (ZA) de-escalation. Finally, patients with bone plus extraskeletal metastases showed an erratic variation of NTX, raising concerns that a single ZA regimen might not fit all patients. Future trials should test its effect according to the presence of extraskeletal involvement.

Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.

Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?

Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis.

The role of CYBA (p22phox) and catalase genetic polymorphisms and their possible epistatic interaction in cervical cancer.

Human papillomavirus (HPV) infection is necessary but not a sufficient cause for the development of invasive cervical cancer (ICC). Epithelial tissues, target for HPV, are exposed to reactive oxygen species (ROS) associated with tumor initiation and progression. The NADPH oxidase (NOX) and catalase (CAT) are involved in hydrogen peroxide (H2O2) production and inactivation, respectively. P22phox is the NOX subunit encoded by the CYBA gene that has a functional polymorphism (C-242T). This protein is involved in the regulation of electron transfer to oxygen. CAT is a hemic enzyme that plays a role in regulating H2O2 concentration, with a functional polymorphism (C-262T) in its gene. We evaluated CYBA C-242T and CAT C262T genetic polymorphisms and their interaction in 132 women with ICC. We found that CYBA C-242T and CAT C262T genotype frequencies were significantly different between ICC and controls (χ (2) test, p = 0.017 and p = 0.009, respectively). Women with the C/T CYBA-242 genotype had a lower risk for ICC development (odds ratio (OR) = 0.515, 95% confidence interval (CI) 0.291-0.914, p = 0.023) whereas T/T CAT-262 genotype carriers present an increased risk for ICC (OR = 3.034, 95% CI 1.462-6.298, p = 0.003). Women with C/C genotype for CYBA and T/T genotype for CAT had an increased risk to develop ICC comparing with the interaction of the other possible genotypes of both genes (OR = 3.952, 95% CI 1.075-14.521, p = 0.032). The CYBA C-242T and CAT C-262T genetic polymorphisms and their epistatic interactions can be associated with ICC through mechanisms related with the role of ROS in cell proliferation and apoptosis.

The role of low-molecular-weight protein tyrosine phosphatase (LMW-PTP ACP1) in oncogenesis.

Protein tyrosine phosphorylation is a crucial cellular event that is involved in the most important processes of cellular metabolism. Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) is a tyrosine phosphatase that presents two active distinct isoforms and is regulated through cysteine oxidation and tyrosine phosphorylation. This enzyme has been linked to tumorigenesis, but its role is considered controversial: it may be considered oncogenic or anti-oncogenic depending on its interaction with different substrates. Furthermore, recent studies have demonstrated that LMW-PTP is involved in epithelial cell migration, a characteristic of tumor cells. This fact strengthens the importance of this enzyme in the oncogenic process and opens new avenues for future research. The study of LMW-PTP and its pathways may enhance therapeutic strategies that target tyrosine phosphorylation and its substrates. In this review, we try to clarify the importance of this protein in carcinogenesis through the analysis of LMW-PTP interaction with different substrates.

Cellular uptake mechanisms of an antitumor ruthenium compound: the endosomal/lysosomal system as a target for anticancer metal-based drugs.

Previous studies have described promising antitumor activity of an organometallic Ru(II) complex, η5-cyclopentadienyl(2,2'-bipyridyl)(triphenylphosphane) Ruthenium(II) triflate ([η5-C5H5)Ru(2,2'-bipyridyl)(PPh3)][CF3SO3]) herein designated as TM34. Its broad spectrum of activity against a panel of human tumor cell lines and high antiproliferative efficiency prompted us to focus on its mode of action. We present herein results obtained with two human tumor cell lines A2780 and MDAMB231 on the compound distribution within the cell, the mechanism of its activity, and its cellular targets. The prospective metallodrug TM34 revealed: (a) fast antiproliferative effects even at short incubation times for both cell lines; (b) preferential localization at the cell membrane and cytosol; (c) cellular activity by a temperature-dependent process, probably macropinocytosis; (d) inhibition of a lysosomal enzyme, acid phosphatase, in a dose-dependent mode; and (e) disruption and vesiculation of the Golgi apparatus, which suggest the involvement of the endosomal/lysosomal system in its mode of action. These results are essential to elucidate the basis for the cytotoxic activity and mechanism of action of this Ru(II)(η5-cyclopentadienyl) complex.

The methylenetetrahydrofolate reductase gene variant (C677T) as a susceptibility gene for tetralogy of Fallot.

The aim of this study was to evaluate whether the cytosine-to-thymine mutation at base 677 of the methylenetetrahydrofolate reductase gene (MTHFR C677T), which has been associated with neural tube defects and congenital oral cleft, is also associated with tetralogy of Fallot (TF), a congenital heart disease. The MTHFR C677T genotype was investigated in a sample of 38 children born with TF who underwent surgical repair in early life. Two hundred and fifty-one healthy individuals were included as controls for allele and genotype frequencies. We found a higher prevalence of the T allele in TF compared to the control group (OR = 1.675; 95% CI [1.022-2.743]; p = 0.05). The TT genotype increased by 4.856 the risk for this congenital disease (95% CI 1.308 12.448; p = 0.028). Our results suggest that MTHFR polymorphism can be considered a susceptibility gene for this congenital heart disease.

Exploring the cytotoxic activity of new phenanthroline salicylaldimine Zn(II) complexes.

Zinc(II) complexes bearing N-salicylideneglycinate (Sal-Gly) and 1,10-phenanthroline (phen) or phenanthroline derivatives [NN = 5-chloro-1,10-phenanthroline, 5-amine-1,10-phenanthroline (amphen), 4,7-diphenyl-1,10-phenanthroline (Bphen) and 5,6-epoxy-5,6-dihydro-1,10-phenanthroline] are synthesized. Complexes formulated as [Zn(NN)2(H2O)2]2+(NN = phen and amphen), are also prepared. The cytotoxicity of the compounds is evaluated towards a panel of human cancer cells: ovarian (A2780), breast (MCF7) and cervical (HeLa), as well as non-tumoral V79 fibroblasts. All compounds display higher cytotoxicity than cisplatin (IC50 = 22.5 ±â€¯5.0 µM) towards ovarian cells, showing IC50values in the low micromolar range. Overall, all compounds show higher selectivity for the A2780 cells than for the non-tumoral cells and higher selectivity indexes (IC50(V79)/IC50(A2780) than cisplatin. [Zn(Sal-Gly)(NN)(H2O)] complexes induce caspase-dependent apoptosis in A2780 cells, except [Zn(Sal-Gly)(Bphen)(H2O)], one of the most cytotoxic of the series. The cellular uptake in the ovarian cells analyzed by Inductively Coupled Plasma mass spectrometry indicates different Zn distribution profiles. Transmission electronic microscopy shows mitochondria alterations and apoptotic features consistent with caspase activation; cells incubated with [Zn(Sal-Gly)(amphen)(H2O)] present additional nuclear membrane alterations in agreement with significant association with the nucleus. The increase of reactive oxygen species and lipid peroxidation forms could be related to apoptosis induction. [Zn(NN)2(H2O)2]2+complexes have high ability to bind DNA through intercalation/groove binding, and circular dichroism data suggests that the main type of species that interact with DNA is [Zn(NN)]2+. Studies varying the % of fetal bovine serum (1-15%) in cell media show that albumin binding decreases the complex activity, indicating that distinct speciation of Zn- and phen-containing species in cell media may affect the cytotoxicity.

Total Knockdown of LMW-PTP in MDA-MB-231 Cells Reduces Osteoclastogenesis.

BACKGROUND: Low molecular weight protein tyrosine phosphatase (LMW-PTP) has been related to tumorigenesis, having both oncogenic and anti-oncogenic roles. The differential roles of its main active isoforms (fast and slow) may account for these discrepancies. The fast isoform has been described to be involved in the bone-metastatic process, although knockdown of the slow isoform was recently reported to reduce osteoclastogenesis. We aimed to study the influence of LMW-PTP isoforms on osteoclast differentiation. MATERIALS AND METHODS: Osteoclast precursors (RAW 264.7) were cultured with conditioned medium from MDA-MB-231 breast cancer cells with total knockdown of LMW-PTP and with knockdown of the slow isoform of LMW-PTP. Tartarate-resistant acid phosphatase (TRAP) staining and quantification were performed to assess osteoclast differentiation. RESULTS: Total knockdown of LMW-PTP, but not of slow LMW-PTP significantly reduced osteoclast differentiation of RAW 264.7 cells. CONCLUSION: We suggest that total LMW-PTP increases osteoclastic differentiation, albeit not at the expense of the slow isoform.

Radionuclides in oncology clinical practice - review of the literature.

Radionuclide therapy is a type of targeted therapy that can be useful in the treatment of several malignant tumors. Compared with other forms of systemic therapy used in cancer - including chemotherapy - it has the advantage of sparing biological structures adjacent to the tumor cells. This treatment modality has registered significant advances since its first use for the treatment of tuberculous skin lesions in the 1900s. This paper reviews the characteristics and clinical applications of therapeutic radionuclides commonly used in the oncology clinical practice, and discusses future potential applications.

Bone metastasis risk factors in breast cancer.

Bone is the single most frequent site for bone metastasis in breast cancer patients. Patients with bone-only metastasis have a fairly good prognosis when compared with patients with visceral disease. Nevertheless, cancer-induced bone disease carries an important risk of developing skeletal related events that impact quality of life (QoL). It is therefore particularly important to stratify patients according to their risk of developing bone metastasis. In this context, several risk factors have been studied, including demographic, clinicopathological, genetic, and metabolic factors. Most of them show conflicting or non-definitive associations and are not validated for clinical use. Nonetheless, tumour intrinsic subtype is widely accepted as a major risk factor for bone metastasis development and luminal breast cancer carries an increased risk for bone disease. Other factors such as gene signatures, expression of specific cytokines (such as bone sialoprotein and bone morphogenetic protein 7) or components of the extracellular matrix (like bone crosslinked C-telopeptide) might also influence the development of bone metastasis. Knowledge of risk factors related with bone disease is of paramount importance as it might be a prediction tool for triggering the use of targeted agents and allow for better patient selection for future clinical trials.

Heteroleptic oxidovanadium(IV) complexes of 2-hydroxynaphtylaldimine and polypyridyl ligands against Trypanosoma cruzi and prostate cancer cells.

In Latin America Chagas disease is an endemic illness caused by the parasite Trypanosoma cruzi (T. cruzi), killing more people than any other parasitic disease. Current chemotherapies are old and inadequate, thus the development of efficient ones is urgently needed. Vanadium-based complexes have been shown to be a promising approach both against parasitic diseases and cancer and this study aims to achieve significant advances in the pursue of effective compounds. Heteroleptic vanadium complexes of Schiff bases and polypyridine compounds were prepared and their stability in solution evaluated by EPR (Electronic Paramagnetic Resonance) and NMR spectroscopy. Their in vitro activities were evaluated against T. cruzi and a set of cells lines representative of human cancer conditions, namely ovarian, breast and prostate cancer. In T. cruzi, most of the complexes depicted IC50 values in the low µM range, induced changes of mitochondrial membrane potential and apoptosis. In cancer cells, complexes showed good to moderate activity and in metastatic cells (prostate PC3), some complexes inhibited the migratory ability, this suggesting that they display antimetastatic potential. Interestingly, complex 5 seemed to have a dual effect being the most cytotoxic complex on all cancer cells and also the most active anti-T-cruzi compound of the series. Globally the complexes showed promising anticancer and anti T. cruzi activities and also displayed some characteristics indicating they are worth to be further explored as antimetastatic drugs.

New Cu(II) complexes with pyrazolyl derived Schiff base ligands: Synthesis and biological evaluation.

Since the discovery of cisplatin there has been a continuous pursuit for new metallodrugs showing higher efficacies and lower side effects. In this work, new copper(II) complexes (C1-C6) of Schiff bases derived from pyrazolyl were developed. Through condensation of 5-methyl-1H-pyrazole-3-carbohydrazide with different aromatic aldehydes - pyridoxal, salicylaldehyde, 3-methoxy-2-hydroxybenzaldehyde, 3-ethoxy-2-hydroxybenzaldehyde and 2-hydroxynaphthene-1-carbaldehyde - a set of new pyrazole based "ONO" tridentate Schiff bases were obtained in moderate to good yields - L1-L6, as well as their Cu(II)-complexes. All compounds were characterized by analytical techniques and their molecular formulae established. The antioxidant potential of all compounds was tested, yielding low activity in most cases, with the exception of L1 and C5. The Cu(II) complexes were tested for their aqueous stability, and for their interaction with biological molecules, namely DNA and HSA (human serum albumin), through fluorescence quenching experiments (and electrophoresis for DNA). With the exception of C3, all the synthesized complexes were able to interact with DNA and HSA. Their cytotoxic activity against two cancer cell lines (MCF7 - breast and PC3 - prostate) was also evaluated. Complexes C5 and C6, with larger aromatic systems, showed much higher cytotoxicity (in the low µM range), than C1-C4, as well as IC50 values much lower than cisplatin. For C6 the results suggest that the mechanisms of cell death do not seem to be mediated by apoptosis, through caspases 3/7 activation, but by involving membrane potential and imbalance in physiological elements such as P, K and Ca.

Low Molecular Weight Protein Tyrosine Phosphatase Slow Isoform Knockdown in MDA-MB-435 Cells Decreases RAW 264.7 Osteoclastic Differentiation.

BACKGROUND/AIM: During the bone metastatic process, tumor cells and bone cells drive a vicious cycle stimulating growth and activity of each other. We here address how low molecular weight protein tyrosine phosphatase (LMW-PTP) could be involved in this process. MATERIALS AND METHODS: We targeted LMW-PTP by siRNA and evaluated the effect of various soluble factors released to the culture medium by the MDA-MB-435 breast cancer cell line, in RAW 264.7 osteoclastogenesis. RESULTS: We showed that these soluble factors did not change RAW 264.7 osteoclastogenic potential. The knockdown of the LMW-PTP slow isoform decreased osteoclastogenesis of RAW 264.7, showing less active Src. The knockdown of LMW-PTP and its slow isoform decreased the release of IL-8 but not IL-6 in MDA-MB-435. CONCLUSION: The LMW-PTP slow isoform can be an important protein in bone metastatic disease, with a fundamental role in the interplay between tumor cells and osteoclasts, through the regulation of Src activity and IL-8 secretion.

Epistatic Interaction of CYP1A1 and COMT Polymorphisms in Cervical Cancer.

There is a clear association between the excessive and cumulative exposure to estrogens and the development of cancer in hormone-sensitive tissues, such as the cervix. We studied the association of CYP1A1 M1 (rs4646903) and COMT (rs4680) polymorphisms in 130 cervical cancer cases (c-cancer) and 179 controls. The CYP1A1 TT genotype was associated with a lower risk for c-cancer (OR = 0.39, p = 0.002). The allele C of CYP1A1 was a risk for c-cancer (OR = 2.29, p = 0.002). Women with COMT LL genotype had a higher risk of developing c-cancer (OR = 4.83, p < 0.001). For the interaction of the CYP1A1&COMT, we observed that TC&HL genotypes had a greater risk for c-cancer (OR = 6.07, p = 0.006) and TT&HL genotypes had a protection effect (OR = 0.24, p < 0.001). The CYP1A1 TT and COMT LL genotypes had higher estradiol levels in c-cancer (p < 0.001 and p = 0.037, resp.). C-cancer is associated with less production of 2-methoxy-estradiol resultant of functional polymorphisms of CYP1A1 and COMT, separately. CYP1A1 and COMT work in a metabolic sequence and their interaction could lead to an alternative pathway of estrogen metabolism with production of 16-OH-estrone that is more proliferative.