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. 2013 May 21;14(5):10483-96.
doi: 10.3390/ijms140510483.

Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone

Peter S Kirk  1 , Theodore Koreckij, Holly M Nguyen, Lisha G Brown, Linda A Snyder, Robert L Vessella, Eva Corey
Affiliations

Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone (V体育ios版)

Peter S Kirk et al. Int J Mol Sci. .

Abstract

The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel VSports手机版. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa. .

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Figures (V体育2025版)

Figure 1
Figure 1
Effects of treatment on serum prostate-specific antigen (PSA), proliferation, and survival. Animals were injected with C4-2B cells directly into tibiae. Once tumors were established (based on serum PSA measurement), animals were randomized into treatment groups as described in the Methods Section. Serum PSA levels were normalized to enrollment values to minimize baseline differences. Normalized serum PSA levels plotted as mean ± SEM. (A) PSA response during the treatment period. Serum PSA levels were significantly lower in all treatment groups vs. control group starting at one week of treatment (p < 0.05); (B) Treatments resulted in significant differences in serum PSA levels at day 70 (control group set to 1); (C) After the treatments were stopped at day 70, a subset of animals was followed to evaluate any lasting effects of the treatments. Administration of CCL2 blockade and its combination with docetaxel showed sustained inhibition of tumor re-growth up to nine weeks following treatment termination; (D) The combination of CCL2 blockade and docetaxel had the most pronounced inhibitory effects on tumor growth as demonstrated by lowest levels of terminal serum PSA levels (control group set to 1); (E) Ki67 staining in untreated control tumors and treated tumors. Three areas of 4–6 samples per group were evaluated with 100–200 cells per area and percentage of positive cells was calculated. Decreased Ki67 positivity was detected in tumors treated with CCL2 blockade alone or in combination with docetaxel at the end of the treatment period, but positivity increased by the end of the follow up period, indicating future recurrence of the tumors; (F) Log-rank test of survival analysis shows significant survival benefits (CCL2: p = 0.0021, CCL2 + DOC: p = 0.0003) conferred by CCL2 blockade and its combination with docetaxel treatment.
Figure 1
Figure 1
Effects of treatment on serum prostate-specific antigen (PSA), proliferation, and survival. Animals were injected with C4-2B cells directly into tibiae. Once tumors were established (based on serum PSA measurement), animals were randomized into treatment groups as described in the Methods Section. Serum PSA levels were normalized to enrollment values to minimize baseline differences. Normalized serum PSA levels plotted as mean ± SEM. (A) PSA response during the treatment period. Serum PSA levels were significantly lower in all treatment groups vs. control group starting at one week of treatment (p < 0.05); (B) Treatments resulted in significant differences in serum PSA levels at day 70 (control group set to 1); (C) After the treatments were stopped at day 70, a subset of animals was followed to evaluate any lasting effects of the treatments. Administration of CCL2 blockade and its combination with docetaxel showed sustained inhibition of tumor re-growth up to nine weeks following treatment termination; (D) The combination of CCL2 blockade and docetaxel had the most pronounced inhibitory effects on tumor growth as demonstrated by lowest levels of terminal serum PSA levels (control group set to 1); (E) Ki67 staining in untreated control tumors and treated tumors. Three areas of 4–6 samples per group were evaluated with 100–200 cells per area and percentage of positive cells was calculated. Decreased Ki67 positivity was detected in tumors treated with CCL2 blockade alone or in combination with docetaxel at the end of the treatment period, but positivity increased by the end of the follow up period, indicating future recurrence of the tumors; (F) Log-rank test of survival analysis shows significant survival benefits (CCL2: p = 0.0021, CCL2 + DOC: p = 0.0003) conferred by CCL2 blockade and its combination with docetaxel treatment.
Figure 2
Figure 2
Effects of treatment on cell morphology and AR immunoreactivity. (a) C4-2B cells in the bone marrow are minimally differentiated cells organized in solid sheets. Cytologically, these tumor cells show high mitotic rate, moderate nucleus:cytoplasm ratio (N/C ratio) and prominent nucleoli. Most of the tumor cells exhibit moderate to intense nuclear AR immunoreactivity. Docetaxel treatment altered the tumor cells, resulting in slight variability in size and shape and decreased percentage and intensity of AR nuclear immunoreactivity. CCL2 blockade caused cytoplasmic vacuolar changes of tumor cells with abundant, transparent cytoplasm and nuclei compressed eccentrically by the large cytoplasmic vacuole. Weak AR nuclear immunoreactivity was detected in the nuclei. Some immunoreactivity was also detected on the cell membrane. We hypothesize that this membrane staining could result from cross reactivity of the treatment antibodies with the detection antibodies. The most pronounced morphological changes were caused by the combination of CCL2 blockade and docetaxel. Severe vacuolar change of the cytoplasm compressed the nuclei into crescent shapes. Low expression AR nuclear immunoreactivity is present in the tumor cells; (b) Nine weeks after treatment cessation, C4-2B cells treated with docetaxel exhibit “foamy”-looking cytoplasm and nuclei, and further loss of nuclear AR is dramatic in this group. Tumor cells treated with CCL2 blockade show vacuolar changes in the cytoplasm, with AR immunoreactivity mostly located in the nuclei with less intense staining in comparison to the cells at the end of the treatment. Membrane immunoreactivity is not present. Pronounced changes are evident in tumors from the combination group. Vacuolar change of the cytoplasm and foamy change of the nuclei are the main features of the tumor cells. AR immunoreactivity is located in the nuclei with moderate expression in more than 90% of the tumor cell population.
Figure 3
Figure 3
Effects of treatment on bone mineral density (a) Representative example radiographs of the tumored tibiae are shown. C4-2B cell growth in the tibiae results in mixed lytic/blastic lesions with expansion of the tibiae. CCL2 blockade decreased changes in the bone caused by the tumors; (b) C4-2B cells growing untreated in tibiae typically result in decreases in BMD. All the treatments examined here significantly attenuate these decreases in BMD, with more pronounced effects detected in the groups receiving CCL2 blockade alone or in combination; (c) Administration of CCL2 blockade causes significant increases in BMD of normal bone as demonstrated by measurements of BMD in contralateral non-tumored tibiae.
Figure 4
Figure 4
Effects of treatment on body weight. (a) Growth of C4-2B cells in tibiae causes weight loss in the control animals, an effect which is abrogated by blockade of CCL2 signaling. Docetaxel does not inhibit this weight loss, despite inhibiting tumor growth; (b) Even after treatment was stopped, those animals originally receiving CCL2 blockade had significantly higher body weights compared to control animals or animals treated with docetaxel.
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