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. 2014 Jun 15;192(12):6111-9.
doi: 10.4049/jimmunol.1302895. Epub 2014 May 14.

Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia

Alex G Cuenca  1 , Angela L Cuenca  1 , Robert D Winfield  1 , Dallas N Joiner  1 , Lori Gentile  1 , Matthew J Delano  1 , Kindra M Kelly-Scumpia  1 , Philip O Scumpia  1 , Michael K Matheny  2 , Philip J Scarpace  2 , Lizette Vila  3 , Philip A Efron  1 , Drake M LaFace  4 , Lyle L Moldawer  5
Affiliations

Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia

Alex G Cuenca et al. J Immunol. .

Abstract

Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death VSports手机版. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection. .

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"VSports注册入口" Conflict of interest statement

Conflict of Interest: The authors have no conflicts of interest to declare

Figures

Figure 1
Figure 1. In vivo growth kinetics of 4T1 and 66C4 mammary carcinoma
4T1 and 66C4 tumor cells were inoculated into Balb/c mice and followed for 35 days. (A and C) Body and Tumor weight measurements were taken at seven day intervals up to day 35. (B and D) Spleens were harvested from animals and assayed via flow cytometry for MDSCs also at seven day intervals (Gr-1+,CD11b+). Values represent percentage of live cells ± SD (n=5). (E) Comparison of primary tumor burden at day 35 post 66C4 inoculation and day 28 post 4T1 inoculation (NS: Not Significant) (F) Comparison of primary tumor burden at day 35 post 66C4 inoculation and day 28 post 4T1 inoculation (NS=Not Significant) (G) Primary tumors and lungs from 4T1 (28 days post inoculation) and 66C4 (35 days post inoculation).
Figure 2
Figure 2. Changes in body composition, increased oxygen consumption and increased acute phase responses in 4T1-bearing but not 66C4-bearing animals
(A) 4T1-, 66C4-, and nontumor- (NT) bearing mice were assayed at 0, 14, and 28 days post 4T1 tumor inoculation for total adipose tissue content via TD-NMR. (n=4–5 per group; * Tukey’s One way-ANOVA p <0.001). (B) Oxygen consumption (VO2) per total lean tumor free body weight in 4T1- and 66C4- was measured at 0, 14, and 28 days post 4T1 tumor inoculation. Values represent mean ± SD (n=4–5 per group; * Student’s t-test p =0.004)
Figure 3
Figure 3
(A) Plasma was harvested from 4T1- and 66C4-bearing mice at 0, 7, 14, 21, 28, and 35 days post tumor inoculation and assayed for serum amyloid A and haptoglobin via ELISA. Values represent mean concentration in ng/mL and are ± SD (n=4–5/group) (* Mann- Whitney Rank Sum Test p=0.01) (** Mann Whitney Rank Sum Test p=0.002) (*** Student’s t-test p <0.001). (B) Naïve Balb/c animals were injected intravenously with 1 × 107 magnetically enriched Gr-1+ cells from healthy, nontumor and 4T1-bearing animals at days 1, 3, and 5. Serum was collected at days 2, 4, 6, 10, and 14 and assayed for concentrations of serum amyloid A, haptoglobin, and hemopexin. Hashed lines represent values obtained from sham injections (* p<0.05).
Figure 4
Figure 4. Changes in adiposity, oxygen consumption, and acute phase reactants also occur in other tumor models of cachexia following expansion of Gr-1+CD11b+ cells in the spleen and bone marrow
CT26 and LLC was inoculated into naïve mice and followed for 21 days. Spleen and bone marrow (A and B) were harvested from tumor bearing animals at 7 day intervals and plotted against tumor free body weight (n=5/group). Total host adipose tissue content (C and D) and oxygen consumption (E and F) were measured at 7 day intervals as well. Values represent mean ± SD (n=5/group; * One way ANOVA on ranks p<0.001; ** Kruskall-Wallis One way ANOVA on ranks p=0.002; *** ANOVA on ranks p=0.009). Finally, serum from tumor bearing host was assayed via ELISA for the presence of serum amyloid A (SAA) and Haptoglobin (G) Values represent mean concentration in ng/mL and are ± SD (n=5/group; * One way ANOVA on ranks p<0.05; **Kruskall-Wallis One way ANOVA on ranks p<0.001).
Figure 5
Figure 5. Late stage 4T1-bearing animals have an increased susceptibility to endotoxemia and polymicrobial sepsis compared to 66C4- and nontumor-bearing animals
(A) 4T1-, 66C4- and nontumor- (NT) bearing mice at 28–30 days post tumor inoculation were exposed to sublethal dose of endotoxin (n=20 per group; Fisher’s exact test * p < 0.001) (B) 4T1-, 66C4- and nontumor- (NT) bearing mice at 28–30 days post tumor inoculation were challenged via cecal ligation and puncture (CLP) (n=20 per group; Fisher’s Exact Test * NT vs 4T1 p = 0.014 ** 66C4 vs 4T1 p = 0.031).
Figure 6
Figure 6. Overwhelming MDSC infiltration into lung and liver parenchyma following sublethal endotoxemia
(A) Lungs were harvested from 4T1-, 66C4-, and nontumor- (NT) bearing mice at 0, 6, and 12 hours following sublethal endotoxin adminsitration, fixed in formalin, and stained with hematoxylin and eosin. Images taken at 10×. (B) Lung tissue was harvested from 4T1, 66C4, and NT bearing animals at 0 and 12 hours post LPS challenge and placed in formalin. Tissues were then sectioned and stained with hematoxylin and eosin. Arrows denote zone of necrosis. Images wre taken at 10×. (C) AST serum concentrations from 4T1-, 66C4-, and nontumor- (NT) bearing mice at 0 and 12 hours (*n=5 per group; Tukey’s One way ANOVA p<0.05).
Figure 7
Figure 7. Depletion of MDSCs improves survival to endotoxemia in 4T1 bearing animals
(A) Balb/C J 28 days post 4T1 inoculation were injected with either PBS or clodronate liposomes (Encapsula nanosciences, Nashville TN) IV at 100 uL of Liposome suspension/ 10 g of body weight. Animals were then euthanized after 48 hours. (B) Splenocytes from either clodronate (n=5) or PBS (n=3) injected animals were stained for CD11b+Gr-1+ cells and absolute numbers of MDSCs were then calculated (* Student t-test p<0.001). (C) 4T1 and NT-bearing mice at 28–30 days post tumor inoculation were administered either Clodronate or PBS liposomes IV. After 36–48 hours mice were then injected with LPS (50 µg) ip and followed for 72 hours (* Fisher’s exact test NT vs 4T1 +PBS p<0.001, ** 4T1 + Clodronate vs 4T1 +LPS p =0.013). Panel represents the summary of two experiments.
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References

    1. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, Macdonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. The lancet oncology. 2011 - PubMed (VSports在线直播)
    1. Winfield RD, Delano MJ, Pande K, Scumpia PO, Laface D, Moldawer LL. Myeloid-derived suppressor cells in cancer cachexia syndrome: a new explanation for an old problem. JPEN J Parenter Enteral Nutr. 2008;32:651–655. - PMC - PubMed
    1. Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8:887–899. - "V体育2025版" PubMed
    1. Moldawer LL, Copeland EM., 3rd Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer. 1997;79:1828–1839. - "VSports注册入口" PubMed
    1. Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med. 1975;6:61–64. - PubMed

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