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CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.

Neve Polimeno M, Ierano C, D'Alterio C, Simona Losito N, Napolitano M, Portella L, Scognamiglio G, Tatangelo F, Maria Trotta A, Curley S, Costantini S, Liuzzi R, Izzo F, Scala S - Cell. Mol. Immunol. (2014)

Bottom Line: Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032).In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not.Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.

ABSTRACT
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

No MeSH data available.


Related in: MedlinePlus

CXCR4 and CXCR7 expression in HCC. (a) CXCR4 expression in the peritumoral area (×20). (b) (×20), (c) (×40). Cytoplasmatic and nuclear CXCR4 staining, respectively, in HCC. (d) CXCR7 expression in the peritumoral area (×20). (e) (×20), (f) (×40). CXCR7 expression in HCC. HCC, hepatocellular carcinoma.
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fig1: CXCR4 and CXCR7 expression in HCC. (a) CXCR4 expression in the peritumoral area (×20). (b) (×20), (c) (×40). Cytoplasmatic and nuclear CXCR4 staining, respectively, in HCC. (d) CXCR7 expression in the peritumoral area (×20). (e) (×20), (f) (×40). CXCR7 expression in HCC. HCC, hepatocellular carcinoma.

Mentions: Eighty-six HCC patients were assessed, and the clinical and pathological features are described in Table 1. The pT classification was not available for nine of the patients. Of the remaining patients, 13 (16.9%) presented at pT1 (16.8%), 32 patients at pT2 (41.6%), 27 at pT3 (35.1%) and 5 patients at pT4 (6.5%). Nodule size was categorized as diameter <5 or >5 cm, and Edmondson's grade was classified as low (1–2) or high (3–4). CXCR4 was low in 19/86 patients (22.1%), intermediate in 26/86 (30.2%) and high in 41/86 (47.7%). CXCR7 was low only in 8/86 cases (9.3%), intermediate in 34/86 (44.2%) and high in 40/86 (46.5%). In the peritumoral area, CXCR4 was weakly expressed and localized in the cytoplasm and/or the cell surface, whereas in tumors, CXCR4 was highly expressed and localized to the cytosolic and/or nuclear compartment (Figure 1a–c). CXCR7 showed intense staining in tumors localized in the cytosol (Figure 1d–f). A correlation trend was detected between CXCR4 expression and pT stage (P=0.0519), whereas no correlation was observed between CXCR4 or CXCR7 expression compared to tumor size or Edmondson's grading.


CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.

Neve Polimeno M, Ierano C, D'Alterio C, Simona Losito N, Napolitano M, Portella L, Scognamiglio G, Tatangelo F, Maria Trotta A, Curley S, Costantini S, Liuzzi R, Izzo F, Scala S - Cell. Mol. Immunol. (2014)

CXCR4 and CXCR7 expression in HCC. (a) CXCR4 expression in the peritumoral area (×20). (b) (×20), (c) (×40). Cytoplasmatic and nuclear CXCR4 staining, respectively, in HCC. (d) CXCR7 expression in the peritumoral area (×20). (e) (×20), (f) (×40). CXCR7 expression in HCC. HCC, hepatocellular carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496532&req=5

fig1: CXCR4 and CXCR7 expression in HCC. (a) CXCR4 expression in the peritumoral area (×20). (b) (×20), (c) (×40). Cytoplasmatic and nuclear CXCR4 staining, respectively, in HCC. (d) CXCR7 expression in the peritumoral area (×20). (e) (×20), (f) (×40). CXCR7 expression in HCC. HCC, hepatocellular carcinoma.
Mentions: Eighty-six HCC patients were assessed, and the clinical and pathological features are described in Table 1. The pT classification was not available for nine of the patients. Of the remaining patients, 13 (16.9%) presented at pT1 (16.8%), 32 patients at pT2 (41.6%), 27 at pT3 (35.1%) and 5 patients at pT4 (6.5%). Nodule size was categorized as diameter <5 or >5 cm, and Edmondson's grade was classified as low (1–2) or high (3–4). CXCR4 was low in 19/86 patients (22.1%), intermediate in 26/86 (30.2%) and high in 41/86 (47.7%). CXCR7 was low only in 8/86 cases (9.3%), intermediate in 34/86 (44.2%) and high in 40/86 (46.5%). In the peritumoral area, CXCR4 was weakly expressed and localized in the cytoplasm and/or the cell surface, whereas in tumors, CXCR4 was highly expressed and localized to the cytosolic and/or nuclear compartment (Figure 1a–c). CXCR7 showed intense staining in tumors localized in the cytosol (Figure 1d–f). A correlation trend was detected between CXCR4 expression and pT stage (P=0.0519), whereas no correlation was observed between CXCR4 or CXCR7 expression compared to tumor size or Edmondson's grading.

Bottom Line: Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032).In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not.Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Oncological Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Giovanni Pascale"-IRCCS-ITALIA, Naples, Italy.

ABSTRACT
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

No MeSH data available.


Related in: MedlinePlus