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Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System.

Barbieri F, Thellung S, Würth R, Gatto F, Corsaro A, Villa V, Nizzari M, Albertelli M, Ferone D, Florio T - Int J Endocrinol (2014)

Bottom Line: Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioning via autocrine/paracrine mechanisms was also reported.Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion.Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Medical Specialties and Center of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2-16132 Genova, Italy.

ABSTRACT
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 hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioning via autocrine/paracrine mechanisms was also reported. Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion. In this review we focus on the physiological and pathological functions of immune-related cyto- and chemokines, mainly focusing on the CXCL12/CXCR4-7 axis, and their role in pituitary tumorigenesis. Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.

No MeSH data available.


Related in: MedlinePlus

Overexpression of CXCR4 in human pituitary adenomas as compared to normal human adenohypophysis. Immunohistochemical images of human GH-secreting adenoma showing the marked homogeneous positivity for CXCR4 throughout the tissue as compared to scattered staining evidenced in normal anterior pituitary. Hematoxylin and eosin staining and GH-positivity are also depicted. (Original magnification 40x).
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fig1: Overexpression of CXCR4 in human pituitary adenomas as compared to normal human adenohypophysis. Immunohistochemical images of human GH-secreting adenoma showing the marked homogeneous positivity for CXCR4 throughout the tissue as compared to scattered staining evidenced in normal anterior pituitary. Hematoxylin and eosin staining and GH-positivity are also depicted. (Original magnification 40x).

Mentions: In humans, a slightly different pattern of expression was found in autoptic normal pituitaries. Scattered expression of both CXCR4 and CXCL12 within the anterior lobe was detected by immunohistochemistry, revealing a nonhomogeneous positivity for both proteins throughout the tissue, including large negative areas, others showing few positive cells and rare zones with higher expression [129] (Figure 1). Interestingly, in all these areas, CXCR4 expression resulted largely higher than its ligand, although all the CXCL12-positive cells express CXCR4, as well. CXCR4-expressing cells do not belong to specific secreting cell type, being present in GH, PRL, or ACTH-secreting cells, while no expression was observed in human FS cells. However, some CXCR4-expressing cells do not coexpress any hormones and no colocalization of either CXCR4 or CXCL12 was observed in FS cells; thus it was proposed that CXCL12/CXCR4 system may also label undifferentiated/progenitor cells. Conversely, the rare CXCL12-positive cells were mainly, although not exclusively, corticotrophs [129]. Notably, this CK-receptor pair was undetectable in human posterior pituitary lobe [129], contrarily to what was observed in rats. Thus, from these data it is evident that, in normal pituitary, CXCL12 is secreted by cell subpopulations that, cooperating with hypothalamic factors (including CXCL12 itself), may contribute to paracrine modulation of pituitary functioning (Figure 2). Consequently, alterations of the endocrine regulatory pathways due to upregulation of hypothalamic/pituitary CXCL12/CXCR4 axis might lead to the development of pituitary adenomas [127, 129].


Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System.

Barbieri F, Thellung S, Würth R, Gatto F, Corsaro A, Villa V, Nizzari M, Albertelli M, Ferone D, Florio T - Int J Endocrinol (2014)

Overexpression of CXCR4 in human pituitary adenomas as compared to normal human adenohypophysis. Immunohistochemical images of human GH-secreting adenoma showing the marked homogeneous positivity for CXCR4 throughout the tissue as compared to scattered staining evidenced in normal anterior pituitary. Hematoxylin and eosin staining and GH-positivity are also depicted. (Original magnification 40x).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4248486&req=5

fig1: Overexpression of CXCR4 in human pituitary adenomas as compared to normal human adenohypophysis. Immunohistochemical images of human GH-secreting adenoma showing the marked homogeneous positivity for CXCR4 throughout the tissue as compared to scattered staining evidenced in normal anterior pituitary. Hematoxylin and eosin staining and GH-positivity are also depicted. (Original magnification 40x).
Mentions: In humans, a slightly different pattern of expression was found in autoptic normal pituitaries. Scattered expression of both CXCR4 and CXCL12 within the anterior lobe was detected by immunohistochemistry, revealing a nonhomogeneous positivity for both proteins throughout the tissue, including large negative areas, others showing few positive cells and rare zones with higher expression [129] (Figure 1). Interestingly, in all these areas, CXCR4 expression resulted largely higher than its ligand, although all the CXCL12-positive cells express CXCR4, as well. CXCR4-expressing cells do not belong to specific secreting cell type, being present in GH, PRL, or ACTH-secreting cells, while no expression was observed in human FS cells. However, some CXCR4-expressing cells do not coexpress any hormones and no colocalization of either CXCR4 or CXCL12 was observed in FS cells; thus it was proposed that CXCL12/CXCR4 system may also label undifferentiated/progenitor cells. Conversely, the rare CXCL12-positive cells were mainly, although not exclusively, corticotrophs [129]. Notably, this CK-receptor pair was undetectable in human posterior pituitary lobe [129], contrarily to what was observed in rats. Thus, from these data it is evident that, in normal pituitary, CXCL12 is secreted by cell subpopulations that, cooperating with hypothalamic factors (including CXCL12 itself), may contribute to paracrine modulation of pituitary functioning (Figure 2). Consequently, alterations of the endocrine regulatory pathways due to upregulation of hypothalamic/pituitary CXCL12/CXCR4 axis might lead to the development of pituitary adenomas [127, 129].

Bottom Line: Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioning via autocrine/paracrine mechanisms was also reported.Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion.Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Medical Specialties and Center of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2-16132 Genova, Italy.

ABSTRACT
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 hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioning via autocrine/paracrine mechanisms was also reported. Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion. In this review we focus on the physiological and pathological functions of immune-related cyto- and chemokines, mainly focusing on the CXCL12/CXCR4-7 axis, and their role in pituitary tumorigenesis. Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.

No MeSH data available.


Related in: MedlinePlus