Prognostic impact of CD57, CD68, M-CSF, CSF-1R, Ki67 and TGF-beta in soft tissue sarcomas

BMC Clinical Pathology

Lill-Tove Busund¹  Roy M Bremnes³  Khalid Al-Shibli²  Eivind Smeland²  Tom Donnem³  Andrej Valkov¹  Thomas K Kilvaer¹  Sveinung W Sorbye¹ 

[1] Institute of Medical Biology, University of Tromso, Tromso, Norway;Dept of Pathology, Nordland Central Hospital, Bodo, Norway;Institute of Clinical Medicine, University of Tromso, Tromso, Norway

关键词: TMA;    TGF-beta;    Ki67;    CD57;    NK cells;    Macrophages;    DSS;    Malignancy grade;    STS;    Soft tissue sarcomas;   

Others  :  1085413
DOI  :  10.1186/1472-6890-12-7

 received in 2012-02-17, accepted in 2012-05-03,  发布年份 2012

【 摘 要 】

Background

Prognostic markers in curable STS may have the potential to guide therapy after surgical resection. The purpose of this study was to clarify the prognostic impact of the presence of cells and growth factors belonging to the innate immune system in soft tissue sarcomas (STS). The significance of macrophages (CD68), their growth factor macrophage colony-stimulating factor (M-CSF), its receptor colony-stimulating factor-1 receptor (CSF-1R), natural killer cells (CD57) and the general immunomodulating molecule (TGF-beta) are all controversial in STS. Herein, these markers are evaluated and compared to the cell proliferation marker Ki67.

Methods

Tissue microarrays from 249 patients with non-gastrointestinal (non-GIST) STS were constructed from duplicate cores of viable and representative neoplastic tumor areas and duplicate cores of peritumoral capsule. Immunohistochemistry was used to evaluate the expression of CD68, M-CSF, CSF-1R, CD57, TGF-beta and Ki67 in tumor and peritumoral capsule.

Results

In univariate analyses increased expression of M-CSF (P = 0.034), Ki67 (P < 0.001) and TGF-beta (P = 0.003) in tumor correlated with shorter disease-specific survival (DSS). Increased expression of CD68 in tumor correlated significantly with malignancy grade (P = 0.016), but not DSS (P = 0.270). Increased expression of Ki67 in peritumoral capsule tended to correlate with a shorter DSS (P = 0.057). In multivariate analyses, co-expression of M-CSF and TGF-beta (P = 0.022) in tumor and high expression of Ki67 (P = 0.019) in peritumoral capsule were independent negative prognostic factors for DSS.

Conclusions

Increased co-expression of M-CSF and TGF-beta in tumor in patients with STS, and increased expression of Ki67 in peritumoral capsule were independent negative prognostic factors for DSS.

【 授权许可】

   
2012 Sorbye et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Gustafson P: Soft tissue sarcoma. Epidemiology and prognosis in 508 patients. Acta Orthop Scand Suppl 1994, 259:1-31.
• [2]Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 2009, 59:225-249.
• [3]Dickinson IC, Whitwell DJ, Battistuta D, Thompson B, Strobel N, Duggal A, et al.: Surgical margin and its influence on survival in soft tissue sarcoma. ANZ J Surg 2006, 76:104-109.
• [4]Kiatisevi P, Asavamongkolkul A, Phimolsarnti R, Waikakul S, Benjarassamerote S: The outcomes and prognostic factors of patients with soft-tissue sarcoma. J Med Assoc Thai 2006, 89:334-342.
• [5]Koea JB, Leung D, Lewis JJ, Brennan MF: Histopathologic type: an independent prognostic factor in primary soft tissue sarcoma of the extremity? Ann Surg Oncol 2003, 10:432-440.
• [6]Mendenhall WM, Zlotecki RA, Hochwald SN, Hemming AW, Grobmyer SR, Cance WG: Retroperitoneal soft tissue sarcoma. Cancer 2005, 104:669-675.
• [7]Raney RB, Crist WM, Maurer HM, Foulkes MA: Prognosis of children with soft tissue sarcoma who relapse after achieving a complete response. a report from the Intergroup Rhabdomyosarcoma Study I. Cancer 1983, 52:44-50.
• [8]Yang RS, Lane JM, Eilber FR, Dorey FJ, al Shaikh R, Schumacher LY, et al.: High grade soft tissue sarcoma of the flexor fossae. Size rather than compartmental status determine prognosis. Cancer 1995, 76:1398-1405.
• [9]Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS: Prognostic factors for disease-specific survival after first relapse of soft-tissue sarcoma: analysis of 402 patients with disease relapse after initial conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 2003, 57:739-747.
• [10]Ottaiano A, De Chiara A, Fazioli F, Talamanca AA, Mori S, Botti G, et al.: Biological prognostic factors in adult soft tissue sarcomas. Anticancer Res 2005, 25:4519-4526.
• [11]Salgaller ML: The development of immunotherapies for non-small cell lung cancer. Expert Opin Biol Ther 2002, 2:265-278.
• [12]de Visser KE, Eichten A, Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006, 6:24-37.
• [13]Smyth MJ, Crowe NY, Hayakawa Y, Takeda K, Yagita H, Godfrey DI: NKT cells - conductors of tumor immunity? Curr Opin Immunol 2002, 14:165-171.
• [14]Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, et al.: The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 1997, 79:2320-2328.
• [15]Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al.: Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000, 88:577-583.
• [16]Lv L, Pan K, Li XD, She KL, Zhao JJ, Wang W, et al.: The Accumulation and Prognosis Value of Tumor Infiltrating IL-17 Producing Cells in Esophageal Squamous Cell Carcinoma. PLoS One 2011, 6:e18219.
• [17]Wu J, Lanier LL: Natural killer cells and cancer. Adv Cancer Res 2003, 90:127-156.
• [18]Zhang T, Sentman CL: Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Res 2011, 71:2066-2076.
• [19]Arshad H, Ahmad Z, Hasan SH: Gliomas: correlation of histologic grade, Ki67 and p53 expression with patient survival. Asian Pac J Cancer Prev 2010, 11:1637-1640.
• [20]Aune G, Stunes AK, Tingulstad S, Salvesen O, Syversen U, Torp SH: The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas. Int J Clin Exp Pathol 2011, 4:444-453.
• [21]Karim RZ, Gerega SK, Yang YH, Spillane A, Carmalt H, Scolyer RA, et al.: p16 and pRb immunohistochemical expression increases with increasing tumour grade in mammary phyllodes tumours. Histopathology 2010, 56:868-875.
• [22]Takeshita A, Kimura W, Hirai I, Takasu N, Moriya T, Tezuka K, Watanabe T: Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma. Pancreas 2012, 41(1):114-20.
• [23]Wojnar A, Kobierzycki C, Krolicka A, Pula B, Podhorska-Okolow M, Dziegiel P: Correlation of Ki-67 and MCM-2 proliferative marker expression with grade of histological malignancy (G) in ductal breast cancers. Folia Histochem Cytobiol 2010, 48:442-446.
• [24]Lopez-Guerrero JA, Machado I, Scotlandi K, Noguera R, Pellin A, Navarro S, et al.: Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's sarcoma family of tumors. Int J Cancer 2011, 128:1139-1150.
• [25]Sorbye SW, Kilvaer T, Valkov A, Donnem T, Smeland E, Al-Shibli K, et al.: Prognostic impact of lymphocytes in soft tissue sarcomas. PLoS One 2011, 6:e14611.
• [26]Sorbye SW, Kilvaer TK, Valkov A, Donnem T, Smeland E, Al-Shibli K, et al.: Prognostic impact of peritumoral lymphocyte infiltration in soft tissue sarcomas. BMC Clin Pathol 2012, 12:5. BioMed Central Full Text
• [27]Richardsen E, Sorbye SW, Crowe JP, Yang JL, Busund LT: Expression of M-CSF and CSF-1R is correlated with histological grade in soft tissue tumors. Anticancer Res 2009, 29:3861-3866.
• [28]Bremnes RM, Veve R, Gabrielson E, Hirsch FR, Baron A, Bemis L, et al.: High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer. J Clin Oncol 2002, 20:2417-2428.
• [29]Donnem T, Al Saad S, Al Shibli K, Delghandi MP, Persson M, Nilsen MN, et al.: Inverse prognostic impact of angiogenic marker expression in tumor cells versus stromal cells in non small cell lung cancer. Clin Cancer Res 2007, 13:6649-6657.
• [30]Nocito A, Kononen J, Kallioniemi OP, Sauter G: Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer 2001, 94:1-5.
• [31]Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, et al.: Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002, 35:23-28.
• [32]Takanami I, Takeuchi K, Giga M: The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. J Thorac Cardiovasc Surg 2001, 121:1058-1063.
• [33]Al Shibli K, Al Saad S, Donnem T, Persson M, Bremnes RM, Busund LT: The prognostic value of intraepithelial and stromal innate immune system cells in non-small cell lung carcinoma. Histopathology 2009, 55:301-312.
• [34]Focosi D, Bestagno M, Burrone O, Petrini M: CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol 2010, 87:107-116.
• [35]Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, et al.: CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood 2010, 116:3865-3874.
• [36]Pei XH, Nakanishi Y, Takayama K, Bai F, Hara N: Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors can stimulate the invasive capacity of human lung cancer cells. Br J Cancer 1999, 79:40-46.
• [37]Kaminska J, Kowalska M, Kotowicz B, Fuksiewicz M, Glogowski M, Wojcik E, et al.: Pretreatment serum levels of cytokines and cytokine receptors in patients with non-small cell lung cancer, and correlations with clinicopathological features and prognosis. M-. Oncology 2006, 70:115-125.
• [38]Yagiz K, Rittling SR: Both cell-surface and secreted CSF-1 expressed by tumor cells metastatic to bone can contribute to osteoclast activation. Exp Cell Res 2009, 315:2442-2452.
• [39]Kirma N, Hammes LS, Liu YG, Nair HB, Valente PT, Kumar S, et al.: Elevated expression of the oncogene c-fms and its ligand, the macrophage colony-stimulating factor-1, in cervical cancer and the role of transforming growth factor-beta1 in inducing c-fms expression. Cancer Res 2007, 67:1918-1926.
• [40]Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, et al.: A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol 2009, 11:943-950.
• [41]Massague J: TGFbeta in Cancer. Cell 2008, 134:215-230.
• [42]Valkov A, Sorbye SW, Kilvaer TK, Donnem T, Smeland E, Bremnes RM, et al.: The prognostic impact of TGF-beta1, fascin. NF-kappaB and PKC-zeta expression in soft tissue sarcomas. PLoS One 2011, 6:e17507.
• [43]Grayfer L, Hanington PC, Belosevic M: Macrophage colony-stimulating factor (CSF-1) induces pro-inflammatory gene expression and enhances antimicrobial responses of goldfish (Carassius auratus L.) macrophages. Fish Shellfish Immunol 2009, 26:406-413.
• [44]Olivares J, Kumar P, Yu Y, Maples PB, Senzer N, Bedell C, et al.: Phase I trial of TGF-beta 2 antisense GM-CSF gene-modified autologous tumor cell (TAG) vaccine. Clin Cancer Res 2011, 17:183-192.
• [45]Gontero P, Sidhu PS, Muir GH: Penile fracture repair: assessment of early results and complications using color Doppler ultrasound. Int J Impot Res 2000, 12:125-128.
• [46]Bremnes RM, Donnem T, Al Saad S, Al Shibli K, Andersen S, Sirera R, et al.: The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 2011, 6:209-217.