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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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Immunohistochemical staining of pVEGFR-1 in tumor cells and VEGFR-1 in inflammatory cells of CC tissue. (A) Characteristic pVEGFR-1Tyr1048 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (B) Characteristic pVEGFR-1Tyr1213 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (C) Characteristic pVEGFR-1Tyr1333 expression in tumor cells with nuclear immunostaining (x 400). (D) pVEGFR-1 expression in tumor cells in tumor budding regions. Tumor budding was defined as single tumor cells and oligocellular tumor cell clusters along the invasive margin (D1, H.E., x 200). Expression of pVEGFR-1Tyr1048 (D2, x 200) and pVEGFR-1Tyr1213 (D3, x 200) in tumor budding regions. (E) Characteristic VEGFR-1 expression in inflammatory cells. Lymph follicles along the invasive front (E1, H.E., x 40) with VEGFR-1 immunopositivity (E2, x 100) in a non-metastatic CC case.
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Fig1: Immunohistochemical staining of pVEGFR-1 in tumor cells and VEGFR-1 in inflammatory cells of CC tissue. (A) Characteristic pVEGFR-1Tyr1048 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (B) Characteristic pVEGFR-1Tyr1213 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (C) Characteristic pVEGFR-1Tyr1333 expression in tumor cells with nuclear immunostaining (x 400). (D) pVEGFR-1 expression in tumor cells in tumor budding regions. Tumor budding was defined as single tumor cells and oligocellular tumor cell clusters along the invasive margin (D1, H.E., x 200). Expression of pVEGFR-1Tyr1048 (D2, x 200) and pVEGFR-1Tyr1213 (D3, x 200) in tumor budding regions. (E) Characteristic VEGFR-1 expression in inflammatory cells. Lymph follicles along the invasive front (E1, H.E., x 40) with VEGFR-1 immunopositivity (E2, x 100) in a non-metastatic CC case.

Mentions: In the tumor center and tumor budding regions 87% and 94% of the CC, respectively, have shown a positive VEGFR-1 cytoplasmatic expression (Table 4). Negative VEGFR-1 expression in the tumor core was associated with lymphogenous metastasis (p = 0.03). From the 37 investigated N0/M0 cases 27 CC exhibited tumor budding. Interestingly, from the 10 cases without this histopathological feature, 9 tumors were characterized by positive VEGFR-1 expression. Consequently, in the tumor budding regions significant differences did not exist between non-metastatic and metastatic status. The VEGFR-1 phosphorylated at Tyr1048 and Ty1213 exhibited a submembranous accentuated cytoplasmatic and at Tyr1333 a specific nuclear immunoreactivity (Figure1A-C). Positive pVEGFR-1Tyr1048, pVEGFR-1Tyr1213 and pVEGFR-1Tyr1333 expression was seen in 74%, 64% and 55%, respectively (Table 4). Negative pVEGFR-1Tyr1048 and pVEGFR-1Tyr1213 immunoreactivity was significantly correlated with distant metastatic stage (p = 0.01). In the tumor budding regions the percentage distribution of positive pVEGFR-1 expression in the same sequence as above was 71%, 64% and 47%, respectively, and thus almost identical (Table 4, Figure 1D). From the 4 N+ CC without the presence of tumor budding 3 expressed strong immunostaining levels. This led to an additional statistical significance for pVEGFR-1Tyr1048 in tumor budding regions between N0/M0 and N+ CC (p = 0.01). pVEGFR-1Tyr1333 immunoreactivity had similar immunointensity distribution throughout all comparative groups.Table 4


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 pVEGFR-1 in tumor cells and VEGFR-1 in inflammatory cells of CC tissue. (A) Characteristic pVEGFR-1Tyr1048 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (B) Characteristic pVEGFR-1Tyr1213 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (C) Characteristic pVEGFR-1Tyr1333 expression in tumor cells with nuclear immunostaining (x 400). (D) pVEGFR-1 expression in tumor cells in tumor budding regions. Tumor budding was defined as single tumor cells and oligocellular tumor cell clusters along the invasive margin (D1, H.E., x 200). Expression of pVEGFR-1Tyr1048 (D2, x 200) and pVEGFR-1Tyr1213 (D3, x 200) in tumor budding regions. (E) Characteristic VEGFR-1 expression in inflammatory cells. Lymph follicles along the invasive front (E1, H.E., x 40) with VEGFR-1 immunopositivity (E2, x 100) in a non-metastatic CC case.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Immunohistochemical staining of pVEGFR-1 in tumor cells and VEGFR-1 in inflammatory cells of CC tissue. (A) Characteristic pVEGFR-1Tyr1048 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (B) Characteristic pVEGFR-1Tyr1213 expression in tumor cells with membranous and cytoplasmic immunostaining (x 400). (C) Characteristic pVEGFR-1Tyr1333 expression in tumor cells with nuclear immunostaining (x 400). (D) pVEGFR-1 expression in tumor cells in tumor budding regions. Tumor budding was defined as single tumor cells and oligocellular tumor cell clusters along the invasive margin (D1, H.E., x 200). Expression of pVEGFR-1Tyr1048 (D2, x 200) and pVEGFR-1Tyr1213 (D3, x 200) in tumor budding regions. (E) Characteristic VEGFR-1 expression in inflammatory cells. Lymph follicles along the invasive front (E1, H.E., x 40) with VEGFR-1 immunopositivity (E2, x 100) in a non-metastatic CC case.
Mentions: In the tumor center and tumor budding regions 87% and 94% of the CC, respectively, have shown a positive VEGFR-1 cytoplasmatic expression (Table 4). Negative VEGFR-1 expression in the tumor core was associated with lymphogenous metastasis (p = 0.03). From the 37 investigated N0/M0 cases 27 CC exhibited tumor budding. Interestingly, from the 10 cases without this histopathological feature, 9 tumors were characterized by positive VEGFR-1 expression. Consequently, in the tumor budding regions significant differences did not exist between non-metastatic and metastatic status. The VEGFR-1 phosphorylated at Tyr1048 and Ty1213 exhibited a submembranous accentuated cytoplasmatic and at Tyr1333 a specific nuclear immunoreactivity (Figure1A-C). Positive pVEGFR-1Tyr1048, pVEGFR-1Tyr1213 and pVEGFR-1Tyr1333 expression was seen in 74%, 64% and 55%, respectively (Table 4). Negative pVEGFR-1Tyr1048 and pVEGFR-1Tyr1213 immunoreactivity was significantly correlated with distant metastatic stage (p = 0.01). In the tumor budding regions the percentage distribution of positive pVEGFR-1 expression in the same sequence as above was 71%, 64% and 47%, respectively, and thus almost identical (Table 4, Figure 1D). From the 4 N+ CC without the presence of tumor budding 3 expressed strong immunostaining levels. This led to an additional statistical significance for pVEGFR-1Tyr1048 in tumor budding regions between N0/M0 and N+ CC (p = 0.01). pVEGFR-1Tyr1333 immunoreactivity had similar immunointensity distribution throughout all comparative groups.Table 4

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