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Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis.

Jayasinghe C, Simiantonaki N, Kirkpatrick CJ - BMC Cancer (2015)

Bottom Line: The effects of VEGF receptors after ligand binding are mediated through receptor tyrosine autophosphorylation.Paracrine-acting VEGF-B production by intratumorally located small vessels and autocrine-acting PlGF production by extratumorally located small vessels seem to be associated with the non-metastatic phenotype.Lymphocyte-associated VEGFR-1 expression in the invasive front without accompanying autophosphorylation could prevent against distant metastasis possibly by acting as a decoy and scavenger receptor.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55101, Mainz, Germany. c.jayasinghe@gmx.de.

ABSTRACT

Background: Detailed knowledge of the essential pro-angiogenic biomolecules, the vascular endothelial growth factor (VEGF) family and its receptors, in the characteristically heterogeneous tumor tissue is a pre-requisite for an effective personalized target therapy. The effects of VEGF receptors after ligand binding are mediated through receptor tyrosine autophosphorylation. We determined the relevance of the VEGFR-1 activating pathway for colon cancer (CC) metastasis.

Methods: The expression profiles of VEGFR-1, phosphorylated (activated) VEGFR-1 (pVEGFR-1(Tyr1048), pVEGFR-1(Tyr1213) and pVEGFR-1(Tyr1333)) and the VEGFR-1 ligands (VEGF, PlGF and VEGF-B) were investigated using immunohistochemistry in different tumor compartments (intratumoral - invasive front - extratumoral), cell types (tumor cells - macro- (large and small vessels) and the microvasculature (capillaries) - inflammatory cells) in human sporadic non-metastatic, lymphogenous metastatic and haematogenous metastatic CC.

Results: VEGF and PlGF produced by tumor cells have an autocrine affinity for their receptor VEGFR-1. Subsequent PlGF-mediated receptor activation by autophosphorylation at Tyr1048 and Tyr1213 is a potential signaling pathway, which in turn seems to protect against distant metastasis and, in regions of tumor budding, additionally against lymph node metastasis. This autocrine link could be supported by possible formation of PlGF-VEGF heterodimers and PlGF-PlGF homodimers, which are known to have anti-metastatic properties. In contrast, in order to enhance their potential for distant metastasis tumor cells produce paracrine-acting VEGF-B. VEGFR-1 activation in tumor-associated macrovasculature but not capillaries appears to affect metastatic ability. Paracrine-mediated receptor autophosphorylation at Tyr1048 and Tyr1213 in small vessels located intratumorally and along the invasive front appears to be inversely correlated with metastasis, especially distant metastasis. Additionally, macrovessels are able to produce VEGFR-1 ligands, which influence the metastatic potential. Paracrine-acting VEGF-B production by intratumorally located small vessels and autocrine-acting PlGF production by extratumorally located small vessels seem to be associated with the non-metastatic phenotype. In contrast, VEGF-B-expressing extratumoral large and small vessels correlate with distant metastasis. Lymphocyte-associated VEGFR-1 expression in the invasive front without accompanying autophosphorylation could prevent against distant metastasis possibly by acting as a decoy and scavenger receptor.

Conclusion: VEGFR-1 and its ligands participate in vascular, tumor cell-mediated and immuno-inflammatory processes in a complex biomolecule-dependent and tumor zone-specific manner and hence could influence metastatic behavior in CC.

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Related in: MedlinePlus

Immunohistochemical staining of the VEGFR-1 ligands and pVEGFR-1 in the vasculature of CC tissue. (A) Characteristic endothelial VEGF expression. VEGF positive intratumoral microvascular vessels with predominantly compressed lumina (A1, x 100) and extratumoral microvascular vessels with open lumina (A2, x 100). (B) Characteristic endothelial PlGF expression: Macrovascular vessels with arteriosclerotic changes (B1, H.E., x 40) and PlGF immunopositivity (B2, x 40) as well as altered macrovascular vessels with discontinuous, hypoplastic smooth muscle cell layer (B3, H.E., x 40) and PlGF immunopositivity (B4, x 40). (C) Characteristic endothelial VEGF-B expression: Small and large vessels with VEGF-B immunopositivity (C1, x 100) and capillaries with absent VEGF-B expression (C2, x100). (D) Characteristic endothelial pVEGFR-1Tyr1048 expression in small intratumoral vessels (x 100). (E) Characteristic endothelial pVEGFR-1Tyr1213 expression in small intratumoral vessels (x 100).
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Fig3: Immunohistochemical staining of the VEGFR-1 ligands and pVEGFR-1 in the vasculature of CC tissue. (A) Characteristic endothelial VEGF expression. VEGF positive intratumoral microvascular vessels with predominantly compressed lumina (A1, x 100) and extratumoral microvascular vessels with open lumina (A2, x 100). (B) Characteristic endothelial PlGF expression: Macrovascular vessels with arteriosclerotic changes (B1, H.E., x 40) and PlGF immunopositivity (B2, x 40) as well as altered macrovascular vessels with discontinuous, hypoplastic smooth muscle cell layer (B3, H.E., x 40) and PlGF immunopositivity (B4, x 40). (C) Characteristic endothelial VEGF-B expression: Small and large vessels with VEGF-B immunopositivity (C1, x 100) and capillaries with absent VEGF-B expression (C2, x100). (D) Characteristic endothelial pVEGFR-1Tyr1048 expression in small intratumoral vessels (x 100). (E) Characteristic endothelial pVEGFR-1Tyr1213 expression in small intratumoral vessels (x 100).

Mentions: Concerning VEGF, there were markedly more cases with VEGF-expressing macro- and microvascular vessels (N0/M0, M+) at the invasive front compared to the tumor center (Figure 2). In nodal-positive CC (N+) this expression was observed only in the macrovasculature. In comparison with lymph node metastatic CC almost twice as many non-metastatic carcinomas displayed positive VEGF staining of the microvascular vessels in zone 2 (p = 0.02). Intratumoral capillaries within the desmoplastic stroma showed predominantly compressed lumina, although some were partly open (Figure 3A1,2). In contrast, a clear dominance of capillaries with open lumina could be seen in zone 3.Figure 2


Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis.

Jayasinghe C, Simiantonaki N, Kirkpatrick CJ - BMC Cancer (2015)

Immunohistochemical staining of the VEGFR-1 ligands and pVEGFR-1 in the vasculature of CC tissue. (A) Characteristic endothelial VEGF expression. VEGF positive intratumoral microvascular vessels with predominantly compressed lumina (A1, x 100) and extratumoral microvascular vessels with open lumina (A2, x 100). (B) Characteristic endothelial PlGF expression: Macrovascular vessels with arteriosclerotic changes (B1, H.E., x 40) and PlGF immunopositivity (B2, x 40) as well as altered macrovascular vessels with discontinuous, hypoplastic smooth muscle cell layer (B3, H.E., x 40) and PlGF immunopositivity (B4, x 40). (C) Characteristic endothelial VEGF-B expression: Small and large vessels with VEGF-B immunopositivity (C1, x 100) and capillaries with absent VEGF-B expression (C2, x100). (D) Characteristic endothelial pVEGFR-1Tyr1048 expression in small intratumoral vessels (x 100). (E) Characteristic endothelial pVEGFR-1Tyr1213 expression in small intratumoral vessels (x 100).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384349&req=5

Fig3: Immunohistochemical staining of the VEGFR-1 ligands and pVEGFR-1 in the vasculature of CC tissue. (A) Characteristic endothelial VEGF expression. VEGF positive intratumoral microvascular vessels with predominantly compressed lumina (A1, x 100) and extratumoral microvascular vessels with open lumina (A2, x 100). (B) Characteristic endothelial PlGF expression: Macrovascular vessels with arteriosclerotic changes (B1, H.E., x 40) and PlGF immunopositivity (B2, x 40) as well as altered macrovascular vessels with discontinuous, hypoplastic smooth muscle cell layer (B3, H.E., x 40) and PlGF immunopositivity (B4, x 40). (C) Characteristic endothelial VEGF-B expression: Small and large vessels with VEGF-B immunopositivity (C1, x 100) and capillaries with absent VEGF-B expression (C2, x100). (D) Characteristic endothelial pVEGFR-1Tyr1048 expression in small intratumoral vessels (x 100). (E) Characteristic endothelial pVEGFR-1Tyr1213 expression in small intratumoral vessels (x 100).
Mentions: Concerning VEGF, there were markedly more cases with VEGF-expressing macro- and microvascular vessels (N0/M0, M+) at the invasive front compared to the tumor center (Figure 2). In nodal-positive CC (N+) this expression was observed only in the macrovasculature. In comparison with lymph node metastatic CC almost twice as many non-metastatic carcinomas displayed positive VEGF staining of the microvascular vessels in zone 2 (p = 0.02). Intratumoral capillaries within the desmoplastic stroma showed predominantly compressed lumina, although some were partly open (Figure 3A1,2). In contrast, a clear dominance of capillaries with open lumina could be seen in zone 3.Figure 2

Bottom Line: The effects of VEGF receptors after ligand binding are mediated through receptor tyrosine autophosphorylation.Paracrine-acting VEGF-B production by intratumorally located small vessels and autocrine-acting PlGF production by extratumorally located small vessels seem to be associated with the non-metastatic phenotype.Lymphocyte-associated VEGFR-1 expression in the invasive front without accompanying autophosphorylation could prevent against distant metastasis possibly by acting as a decoy and scavenger receptor.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55101, Mainz, Germany. c.jayasinghe@gmx.de.

ABSTRACT

Background: Detailed knowledge of the essential pro-angiogenic biomolecules, the vascular endothelial growth factor (VEGF) family and its receptors, in the characteristically heterogeneous tumor tissue is a pre-requisite for an effective personalized target therapy. The effects of VEGF receptors after ligand binding are mediated through receptor tyrosine autophosphorylation. We determined the relevance of the VEGFR-1 activating pathway for colon cancer (CC) metastasis.

Methods: The expression profiles of VEGFR-1, phosphorylated (activated) VEGFR-1 (pVEGFR-1(Tyr1048), pVEGFR-1(Tyr1213) and pVEGFR-1(Tyr1333)) and the VEGFR-1 ligands (VEGF, PlGF and VEGF-B) were investigated using immunohistochemistry in different tumor compartments (intratumoral - invasive front - extratumoral), cell types (tumor cells - macro- (large and small vessels) and the microvasculature (capillaries) - inflammatory cells) in human sporadic non-metastatic, lymphogenous metastatic and haematogenous metastatic CC.

Results: VEGF and PlGF produced by tumor cells have an autocrine affinity for their receptor VEGFR-1. Subsequent PlGF-mediated receptor activation by autophosphorylation at Tyr1048 and Tyr1213 is a potential signaling pathway, which in turn seems to protect against distant metastasis and, in regions of tumor budding, additionally against lymph node metastasis. This autocrine link could be supported by possible formation of PlGF-VEGF heterodimers and PlGF-PlGF homodimers, which are known to have anti-metastatic properties. In contrast, in order to enhance their potential for distant metastasis tumor cells produce paracrine-acting VEGF-B. VEGFR-1 activation in tumor-associated macrovasculature but not capillaries appears to affect metastatic ability. Paracrine-mediated receptor autophosphorylation at Tyr1048 and Tyr1213 in small vessels located intratumorally and along the invasive front appears to be inversely correlated with metastasis, especially distant metastasis. Additionally, macrovessels are able to produce VEGFR-1 ligands, which influence the metastatic potential. Paracrine-acting VEGF-B production by intratumorally located small vessels and autocrine-acting PlGF production by extratumorally located small vessels seem to be associated with the non-metastatic phenotype. In contrast, VEGF-B-expressing extratumoral large and small vessels correlate with distant metastasis. Lymphocyte-associated VEGFR-1 expression in the invasive front without accompanying autophosphorylation could prevent against distant metastasis possibly by acting as a decoy and scavenger receptor.

Conclusion: VEGFR-1 and its ligands participate in vascular, tumor cell-mediated and immuno-inflammatory processes in a complex biomolecule-dependent and tumor zone-specific manner and hence could influence metastatic behavior in CC.

Show MeSH
Related in: MedlinePlus