The Journal of Clinical Endocrinology & Metabolism
Context Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-g... more Context Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-generation somatostatin receptor ligands, e.g. octreotide (OCT). Objective Head-to-head comparison between OCT and CAB in inhibiting growth hormone (GH) secretion in primary cultures of GH- and GH/PRL-secreting tumors. To investigate the role of somatostatin (SST) and dopamine type 2 (D2R) receptor expression. Design To evaluate the antisecretory effect of OCT and CAB, together with receptor mRNA expression, in 23 tumor cultures. Setting and Patients Acromegaly patients referred to the Erasmus Medical Center (Rotterdam, The Netherlands). Interventions 72-hour OCT and CAB treatment (10 nM). Main Outcome Measures GH concentrations in cell culture media. Results OCT showed a slightly higher efficacy compared with CAB (GH decrease -39.5% vs. -32.5%, p = 0.079). The effect of the two drugs was superimposable in GH/PRL co-secreting tumors (-42.1% vs. -44.8%), where SST1 and D2R had a higher exp...
Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegali... more Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegalic patients display variable degrees of bone structure impairment. In this study, we aim to investigate the usefulness of trabecular bone score (TBS), compared to BMD, in identifying acromegalic patients with impaired lumbar spine trabecular microarchitecture. Forty-four acromegalic patients were investigated for disease control, metabolic and gonadal status, bone metabolism parameters, and the presence of vertebral fractures (VFs). Patients and matched healthy controls underwent BMD and TBS examination. Mean TBS values were lower in patients than in controls (p < 0.001), without significant differences in mean lumbar and femoral BMD. TBS values were significantly higher in controlled patients compared to the uncontrolled ones (p = 0.012). No significant differences were found in bone markers with respect to disease control. Mean TBS or lumbar BMD did not significantly differ in patien...
The Journal of Clinical Endocrinology & Metabolism
Context Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are freque... more Context Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly. Objective To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value. Design Retrospective study. Setting Referral center for pituitary diseases. Patients Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Interventions Multimodal treatment of acromegaly. Main Outcome Measures Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients’ evaluations. Results At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2....
Purpose Sodium is essential to life. However, its dietary excess is detrimental to the cardiovasc... more Purpose Sodium is essential to life. However, its dietary excess is detrimental to the cardiovascular system, and sodium restriction is a crucial step in cardiovascular prevention. Iodine deficiency has been fought worldwide for decades, and substantial success has been achieved introducing the use of iodine-enriched salt. Nevertheless, areas of iodine deficiency persist around the world, both in developing and industrialized countries, and a major concern affecting dietary sodium reduction programs is represented by a possible iodine intake deficiency. There are substantial differences in the source of alimentary iodine among countries, such as iodized salt added, household tap water, seafood, or salt employed in packaged food. It is clear that a sodium-restricted diet can induce differences in terms of iodine intake, depending on the country considered. Moreover, iodine status has undergone relevant changes in many countries in the last years. Methods Systematic review of literature evidence about the possible effects of sodium restriction on population iodine status. Results To date, the available results are conflicting, depending on country, salt iodization policy, as well as time frame of data collection. However, to ensure an optimal iodine supply by salt fortification, without exceeding the current recommendation by World Health Organization for salt intake, seems to be an achievable goal. Conclusion A balanced approach may be obtained by an adequate iodine concentration in fortified salt and by promoting the availability of iodized salt for household consumption and food industry use. In this scenario, updated prospective studies are strongly needed.
BackgroundFirst-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medic... more BackgroundFirst-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medical treatment for acromegaly, recommended in patients with persistent disease after neurosurgery, or when surgical approach is not feasible. Despite the lack of strong recommendations from guidelines and consensus statements, data from national Registries report an increasing use of medical therapy as first-line treatment in acromegaly.ObjectiveWe retrospectively evaluated the potential role of a large number of clinical and radiological parameters in predicting the biochemical response to 6-month treatment with fg-SRLs, in a cohort of naïve acromegaly patients referred to a single tertiary center for pituitary diseases.MethodsUnivariable and multivariable logistic regression and linear regression analyses were performed. Biochemical response was defined based on IGF-1 levels, represented as both categorical (tight control, control, >50% reduction) and continuous (linear % reduction) v...
Background Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST 2 and S... more Background Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST 2 and SST 5 are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST 2 , while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST 5 and SST 2. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors. Methods Critical revision of literature data correlating SST expression with patients' response to SRLs. Results SST 2 expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST 2 immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST 2 in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST 2 expression, pasireotide can act throughout SST 5. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST 2 expression observed in nearly 100% of cases, as well as to the balanced amount of SST 5. In corticotroph tumors, pasireotide mainly act via SST 5 , although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype. Conclusions The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.
Chemokines are chemotactic regulators of immune surveillance in physiological and pathological co... more Chemokines are chemotactic regulators of immune surveillance in physiological and pathological conditions such as inflammation, infection, and cancer. Several chemokines and cognate receptors are constitutively expressed in the central nervous system, not only in glial and endothelial cells but also in neurons, controlling neurogenesis, neurite outgrowth, and axonal guidance during development. In particular, the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, form a functional network that controls plasticity in different brain areas, influencing neurotransmission, neuromodulation, and cell migration, and the dysregulation of this chemokinergic axis is involved in several neurodegenerative, neuroinflammatory, and malignant diseases. CXCR4 primarily mediates the transduction of proliferative signals, while CXCR7 seems to be mainly responsible for scavenging CXCL12. Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences h...
Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and accoun... more Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of pituitary adenomas. Medical therapy with somatostatin analogues (SSAs) effectively reduces TSH secretion in approximately 80% of patients and induces shrinkage in about 45% of tumors. According with previous data, resistance to SSA treatment might be due to heterogeneity in somatostatin receptors (SSTRs) expression. We report the case of TSHoma in a 41-year-old man treated with octreotide LAR that caused a dramatic decrease of TSH and thyroid hormones and tumor shrinkage already after 3 months of pre-surgical therapy. In search of potential molecular determinants of octreotide effectiveness, we measured, in primary cultures from this tumor, SSTR and dopamine D2 receptor (D2R) expression, and octreotide and/or cabergoline effects on TSH secretion and cell proliferation. SSTR5 and D2R expression was higher than SSTR2. Octreotide significantly inhibited TSH secretion more effectively than cabergoline (P \ 0.001), whereas the combined treatment was comparable with cabergoline alone. Similarly, octreotide resulted more effective than cabergoline on cell proliferation, while the combination did not show any additive or synergistic effects. In conclusion, the significant antisecretive and antiproliferative effect of octreotide in this patient might be related to the high expression of SSTR5, in the presence of SSTR2. After reviewing the literature, indeed, in line with previous observations, we hypothesize that SSTR5/SSTR2 ratio in TSHomas may represent a useful marker in predicting the outcome of therapy with SSAs. The role of D2R should be further explored considering that the presence of D2R can influence SSTRs functionality.
Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonis... more Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonists, the available data in prostate cancer (PCa) model systems and clinical studies are few, conflicting and not conclusive. This study investigated the effects of lanreotide and new mono-and bi-specific SRIF agonists on proliferation, ligand-driven SRIF receptor (sst) dimerization and secretory pattern of the IGF system in LNCaP cells, a model of androgendependent PCa. LNCaP expressed all sst s , but sst 4. Among them, sst 1 and sst 3 were inversely regulated by serum concentration. Sst 1 /sst 2 and sst 2 /sst 5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst 1 /sst 2) and BIM-23244 (sst 2 /sst 5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst 2) and BIM-23206 (sst 5) alone or in combination. Treatment with BIM-23296 (sst 1) markedly reduced cell proliferation, whereas exposure to BIM-23704 resulted in a lower cell growth inhibition. The antiproliferative effects of BIM-23244, lanreotide and BIM-23704 were unchanged, reduced and abolished by the sst 2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27 KipI and p21 and down-regulation of protein expression of cyclin E, as well as reduced IGF-I and IGF-II secretion. In particular, the administration of exogenous IGF-I, at variance to IGF-II, counteracted the inhibitory effect on cell proliferation of these compounds. Moreover, SRIF agonists reduced endogenous IGFBP-3 proteolysis. These results show that, in LNCaP cells, activation of sst 1 and sst 2 /sst 5 results in relevant antiproliferative/antisecretive actions. INTRODUCTION Somatostatin (SRIF) is an inhibitory tetradecapeptide hormone with exocrine, endocrine, paracrine, and autocrine activities, which plays an important regulatory role in several cell functions, including inhibition of endocrine secretion and cell proliferation (Hejna et al., 2002; Tejeda et al., 2006). Most of the effects of SRIF and of its currently available analogs are mediated via five different G protein-coupled receptor (GPCRs), codenamed sst 1-5 (Patel 1999). Sst s are expressed in a tissue-and subtype-selective manner in both normal and neoplastic cells, and the majority of SRIF target tissues express multiple sst s (Reubi et al., 2001). Recent data suggest that when sst s are coexpressed may interact forming homo-and hetero-dimers also with other GPCRs, altering their original pharmacological and functional profiles (Krantic et al., 2004). Prostate cancer (PCa) is the most frequently diagnosed malignant neoplasm among men in the Western world and remains the second leading cause of cancer-related deaths, with an incidence estimated at 12% in the European Union and at 29% in the USA (Djavan 2007). In addition to the traditional anti-androgen hormonal therapy, commonly used in androgendependent PCa, some evidence suggest SRIF receptors as a target for imaging and treatment of PCa cancer with SRIF analogs (Kalkner et al., 1998; Nilsson et al., 1995; Thakur et al., 1997). Indeed, sst s have been identified in the smooth muscle nodules of both normal and hyperplastic prostatic tissues (Reubi et al., 1995), in human PCa peritumoral veins (Reubi 2003) and in specimens of primary human PCa with Gleason score ranging from 6 to 10 (Halmos et al., 2000). Few data exist about the selected antiproliferative effect of SRIF and related agonists on PCa model systems. In particular, SRIF was shown to reduce the proliferation of LNCaP cells (Brevini et al., 1993) and adjuvant therapy with lanreotide (sst 2 and partial sst 5 agonist) was found effective in slowing cancer growth in castrated Copenhagen rats bearing Dunning R-3327-H prostate tumors (Bogden et al., 1990). Regarding clinical studies, the results obtained in trials conducted on advanced hormone-refractory prostate cancer patients using lanreotide are conflicting and not conclusive (Figg et al., 1995; Maulard et al., 1995) and thus the ideal
The role of somatostatin and dopamine receptors as molecular targets for the treatment of patient... more The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid s...
Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs... more Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr1/sstr2, sstr2/sstr5, sstr5/dopamine (DA) type 2 receptor (D2R), and sstr2/D2R dimers. BIM-23704 (sstr1- and sstr2-preferential compound) increased the co-immunoprecipitation of sstr1/sstr2 and significantly inhibited proliferation (−30.98%). BIM-23244 (sstr2–sstr5 selective agonist) significantly increased the co-immunoprecipitation of sstr2/sstr5,...
phosphorylation of PITKAP/XB130 and its association with PI3K in cells treated with dibutyryl cAM... more phosphorylation of PITKAP/XB130 and its association with PI3K in cells treated with dibutyryl cAMP for 24 h in the presence of latrunculin B, an actin polymerization inhibitor to disrupt actin cytoskeleton. Treatment with latrunculin B completely inhibited cAMP-dependent c-Src activation followed by decreases in tyrosine phosphorylation of PITKAP/XB130 and its association with p85 PI3K, These results indicated Src family tyrosine kinases phosphorylate PITKAP/XB130 in a cAMP-dependent manner. Interestingly, we found that PITKAP/XB130 was co-localized with F-actin in FRTL-5 cells, and a C-terminal region of PITKAP/XB130 (amino acid residues 775-843) directly bound to F-actin in vitro. The PITKAP/XB130 mutant lacking the F-actin-binding region was phosphorylated and bound to p85 PI3K in NIH3T3 fibroblasts that do not express endogenous PITKAP/XB130, suggesting that F-actin binding of PITKAP/XB130 plays some roles other than modulation of tyrosine phosphorylation of this protein. To elucidate physiological roles of tyrosine phosphorylation of PITKAP/XB130, wild type PITKAP/XB130 or the mutant whose tyrosine residue in the p85-binding motif was substituted to phenylalanine (Y72F) was expressed in NIH3T3 fibroblasts treated with IGF-I, and DNA synthesis was then measured. Overexpression of PITKAP/XB130 enhanced IGF-I-induced DNA synthesis; however, the enhancement was not observed in cells expressing the mutant. Based on these data, we concluded that PI3K activation through c-Srcdependent tyrosine phosphorylation of PITKAP/XB130 followed by its association with PI3K on actin cytoskeleton play novel roles in priming cells to IGFs.
Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells a... more Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibil...
The Journal of Clinical Endocrinology & Metabolism
Context Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-g... more Context Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-generation somatostatin receptor ligands, e.g. octreotide (OCT). Objective Head-to-head comparison between OCT and CAB in inhibiting growth hormone (GH) secretion in primary cultures of GH- and GH/PRL-secreting tumors. To investigate the role of somatostatin (SST) and dopamine type 2 (D2R) receptor expression. Design To evaluate the antisecretory effect of OCT and CAB, together with receptor mRNA expression, in 23 tumor cultures. Setting and Patients Acromegaly patients referred to the Erasmus Medical Center (Rotterdam, The Netherlands). Interventions 72-hour OCT and CAB treatment (10 nM). Main Outcome Measures GH concentrations in cell culture media. Results OCT showed a slightly higher efficacy compared with CAB (GH decrease -39.5% vs. -32.5%, p = 0.079). The effect of the two drugs was superimposable in GH/PRL co-secreting tumors (-42.1% vs. -44.8%), where SST1 and D2R had a higher exp...
Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegali... more Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegalic patients display variable degrees of bone structure impairment. In this study, we aim to investigate the usefulness of trabecular bone score (TBS), compared to BMD, in identifying acromegalic patients with impaired lumbar spine trabecular microarchitecture. Forty-four acromegalic patients were investigated for disease control, metabolic and gonadal status, bone metabolism parameters, and the presence of vertebral fractures (VFs). Patients and matched healthy controls underwent BMD and TBS examination. Mean TBS values were lower in patients than in controls (p < 0.001), without significant differences in mean lumbar and femoral BMD. TBS values were significantly higher in controlled patients compared to the uncontrolled ones (p = 0.012). No significant differences were found in bone markers with respect to disease control. Mean TBS or lumbar BMD did not significantly differ in patien...
The Journal of Clinical Endocrinology & Metabolism
Context Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are freque... more Context Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly. Objective To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value. Design Retrospective study. Setting Referral center for pituitary diseases. Patients Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Interventions Multimodal treatment of acromegaly. Main Outcome Measures Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients’ evaluations. Results At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2....
Purpose Sodium is essential to life. However, its dietary excess is detrimental to the cardiovasc... more Purpose Sodium is essential to life. However, its dietary excess is detrimental to the cardiovascular system, and sodium restriction is a crucial step in cardiovascular prevention. Iodine deficiency has been fought worldwide for decades, and substantial success has been achieved introducing the use of iodine-enriched salt. Nevertheless, areas of iodine deficiency persist around the world, both in developing and industrialized countries, and a major concern affecting dietary sodium reduction programs is represented by a possible iodine intake deficiency. There are substantial differences in the source of alimentary iodine among countries, such as iodized salt added, household tap water, seafood, or salt employed in packaged food. It is clear that a sodium-restricted diet can induce differences in terms of iodine intake, depending on the country considered. Moreover, iodine status has undergone relevant changes in many countries in the last years. Methods Systematic review of literature evidence about the possible effects of sodium restriction on population iodine status. Results To date, the available results are conflicting, depending on country, salt iodization policy, as well as time frame of data collection. However, to ensure an optimal iodine supply by salt fortification, without exceeding the current recommendation by World Health Organization for salt intake, seems to be an achievable goal. Conclusion A balanced approach may be obtained by an adequate iodine concentration in fortified salt and by promoting the availability of iodized salt for household consumption and food industry use. In this scenario, updated prospective studies are strongly needed.
BackgroundFirst-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medic... more BackgroundFirst-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medical treatment for acromegaly, recommended in patients with persistent disease after neurosurgery, or when surgical approach is not feasible. Despite the lack of strong recommendations from guidelines and consensus statements, data from national Registries report an increasing use of medical therapy as first-line treatment in acromegaly.ObjectiveWe retrospectively evaluated the potential role of a large number of clinical and radiological parameters in predicting the biochemical response to 6-month treatment with fg-SRLs, in a cohort of naïve acromegaly patients referred to a single tertiary center for pituitary diseases.MethodsUnivariable and multivariable logistic regression and linear regression analyses were performed. Biochemical response was defined based on IGF-1 levels, represented as both categorical (tight control, control, >50% reduction) and continuous (linear % reduction) v...
Background Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST 2 and S... more Background Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST 2 and SST 5 are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST 2 , while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST 5 and SST 2. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors. Methods Critical revision of literature data correlating SST expression with patients' response to SRLs. Results SST 2 expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST 2 immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST 2 in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST 2 expression, pasireotide can act throughout SST 5. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST 2 expression observed in nearly 100% of cases, as well as to the balanced amount of SST 5. In corticotroph tumors, pasireotide mainly act via SST 5 , although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype. Conclusions The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.
Chemokines are chemotactic regulators of immune surveillance in physiological and pathological co... more Chemokines are chemotactic regulators of immune surveillance in physiological and pathological conditions such as inflammation, infection, and cancer. Several chemokines and cognate receptors are constitutively expressed in the central nervous system, not only in glial and endothelial cells but also in neurons, controlling neurogenesis, neurite outgrowth, and axonal guidance during development. In particular, the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, form a functional network that controls plasticity in different brain areas, influencing neurotransmission, neuromodulation, and cell migration, and the dysregulation of this chemokinergic axis is involved in several neurodegenerative, neuroinflammatory, and malignant diseases. CXCR4 primarily mediates the transduction of proliferative signals, while CXCR7 seems to be mainly responsible for scavenging CXCL12. Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences h...
Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and accoun... more Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of pituitary adenomas. Medical therapy with somatostatin analogues (SSAs) effectively reduces TSH secretion in approximately 80% of patients and induces shrinkage in about 45% of tumors. According with previous data, resistance to SSA treatment might be due to heterogeneity in somatostatin receptors (SSTRs) expression. We report the case of TSHoma in a 41-year-old man treated with octreotide LAR that caused a dramatic decrease of TSH and thyroid hormones and tumor shrinkage already after 3 months of pre-surgical therapy. In search of potential molecular determinants of octreotide effectiveness, we measured, in primary cultures from this tumor, SSTR and dopamine D2 receptor (D2R) expression, and octreotide and/or cabergoline effects on TSH secretion and cell proliferation. SSTR5 and D2R expression was higher than SSTR2. Octreotide significantly inhibited TSH secretion more effectively than cabergoline (P \ 0.001), whereas the combined treatment was comparable with cabergoline alone. Similarly, octreotide resulted more effective than cabergoline on cell proliferation, while the combination did not show any additive or synergistic effects. In conclusion, the significant antisecretive and antiproliferative effect of octreotide in this patient might be related to the high expression of SSTR5, in the presence of SSTR2. After reviewing the literature, indeed, in line with previous observations, we hypothesize that SSTR5/SSTR2 ratio in TSHomas may represent a useful marker in predicting the outcome of therapy with SSAs. The role of D2R should be further explored considering that the presence of D2R can influence SSTRs functionality.
Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonis... more Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonists, the available data in prostate cancer (PCa) model systems and clinical studies are few, conflicting and not conclusive. This study investigated the effects of lanreotide and new mono-and bi-specific SRIF agonists on proliferation, ligand-driven SRIF receptor (sst) dimerization and secretory pattern of the IGF system in LNCaP cells, a model of androgendependent PCa. LNCaP expressed all sst s , but sst 4. Among them, sst 1 and sst 3 were inversely regulated by serum concentration. Sst 1 /sst 2 and sst 2 /sst 5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst 1 /sst 2) and BIM-23244 (sst 2 /sst 5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst 2) and BIM-23206 (sst 5) alone or in combination. Treatment with BIM-23296 (sst 1) markedly reduced cell proliferation, whereas exposure to BIM-23704 resulted in a lower cell growth inhibition. The antiproliferative effects of BIM-23244, lanreotide and BIM-23704 were unchanged, reduced and abolished by the sst 2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27 KipI and p21 and down-regulation of protein expression of cyclin E, as well as reduced IGF-I and IGF-II secretion. In particular, the administration of exogenous IGF-I, at variance to IGF-II, counteracted the inhibitory effect on cell proliferation of these compounds. Moreover, SRIF agonists reduced endogenous IGFBP-3 proteolysis. These results show that, in LNCaP cells, activation of sst 1 and sst 2 /sst 5 results in relevant antiproliferative/antisecretive actions. INTRODUCTION Somatostatin (SRIF) is an inhibitory tetradecapeptide hormone with exocrine, endocrine, paracrine, and autocrine activities, which plays an important regulatory role in several cell functions, including inhibition of endocrine secretion and cell proliferation (Hejna et al., 2002; Tejeda et al., 2006). Most of the effects of SRIF and of its currently available analogs are mediated via five different G protein-coupled receptor (GPCRs), codenamed sst 1-5 (Patel 1999). Sst s are expressed in a tissue-and subtype-selective manner in both normal and neoplastic cells, and the majority of SRIF target tissues express multiple sst s (Reubi et al., 2001). Recent data suggest that when sst s are coexpressed may interact forming homo-and hetero-dimers also with other GPCRs, altering their original pharmacological and functional profiles (Krantic et al., 2004). Prostate cancer (PCa) is the most frequently diagnosed malignant neoplasm among men in the Western world and remains the second leading cause of cancer-related deaths, with an incidence estimated at 12% in the European Union and at 29% in the USA (Djavan 2007). In addition to the traditional anti-androgen hormonal therapy, commonly used in androgendependent PCa, some evidence suggest SRIF receptors as a target for imaging and treatment of PCa cancer with SRIF analogs (Kalkner et al., 1998; Nilsson et al., 1995; Thakur et al., 1997). Indeed, sst s have been identified in the smooth muscle nodules of both normal and hyperplastic prostatic tissues (Reubi et al., 1995), in human PCa peritumoral veins (Reubi 2003) and in specimens of primary human PCa with Gleason score ranging from 6 to 10 (Halmos et al., 2000). Few data exist about the selected antiproliferative effect of SRIF and related agonists on PCa model systems. In particular, SRIF was shown to reduce the proliferation of LNCaP cells (Brevini et al., 1993) and adjuvant therapy with lanreotide (sst 2 and partial sst 5 agonist) was found effective in slowing cancer growth in castrated Copenhagen rats bearing Dunning R-3327-H prostate tumors (Bogden et al., 1990). Regarding clinical studies, the results obtained in trials conducted on advanced hormone-refractory prostate cancer patients using lanreotide are conflicting and not conclusive (Figg et al., 1995; Maulard et al., 1995) and thus the ideal
The role of somatostatin and dopamine receptors as molecular targets for the treatment of patient... more The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid s...
Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs... more Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr1/sstr2, sstr2/sstr5, sstr5/dopamine (DA) type 2 receptor (D2R), and sstr2/D2R dimers. BIM-23704 (sstr1- and sstr2-preferential compound) increased the co-immunoprecipitation of sstr1/sstr2 and significantly inhibited proliferation (−30.98%). BIM-23244 (sstr2–sstr5 selective agonist) significantly increased the co-immunoprecipitation of sstr2/sstr5,...
phosphorylation of PITKAP/XB130 and its association with PI3K in cells treated with dibutyryl cAM... more phosphorylation of PITKAP/XB130 and its association with PI3K in cells treated with dibutyryl cAMP for 24 h in the presence of latrunculin B, an actin polymerization inhibitor to disrupt actin cytoskeleton. Treatment with latrunculin B completely inhibited cAMP-dependent c-Src activation followed by decreases in tyrosine phosphorylation of PITKAP/XB130 and its association with p85 PI3K, These results indicated Src family tyrosine kinases phosphorylate PITKAP/XB130 in a cAMP-dependent manner. Interestingly, we found that PITKAP/XB130 was co-localized with F-actin in FRTL-5 cells, and a C-terminal region of PITKAP/XB130 (amino acid residues 775-843) directly bound to F-actin in vitro. The PITKAP/XB130 mutant lacking the F-actin-binding region was phosphorylated and bound to p85 PI3K in NIH3T3 fibroblasts that do not express endogenous PITKAP/XB130, suggesting that F-actin binding of PITKAP/XB130 plays some roles other than modulation of tyrosine phosphorylation of this protein. To elucidate physiological roles of tyrosine phosphorylation of PITKAP/XB130, wild type PITKAP/XB130 or the mutant whose tyrosine residue in the p85-binding motif was substituted to phenylalanine (Y72F) was expressed in NIH3T3 fibroblasts treated with IGF-I, and DNA synthesis was then measured. Overexpression of PITKAP/XB130 enhanced IGF-I-induced DNA synthesis; however, the enhancement was not observed in cells expressing the mutant. Based on these data, we concluded that PI3K activation through c-Srcdependent tyrosine phosphorylation of PITKAP/XB130 followed by its association with PI3K on actin cytoskeleton play novel roles in priming cells to IGFs.
Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells a... more Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibil...
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Papers by Federico Gatto