Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma

Most malignant tumors evidence infiltration of many macrophages. In this study, we investigated an anti‐inflammatory macrophage phenotype (M2) in clear cell renal cell carcinoma (RCC) using CD163 and CD204 as markers. Immunostaining showed a correlation between the number of CD163+ cells and age, sex, nuclear grade, and TNM classification. High infiltration of CD163+ cells was significantly associated with poor clinical prognosis in univariate analysis but not in multivariate analysis. We also carried out in vitro studies to examine cell–cell interactions between macrophages and cancer cells. Culture supernatants from RCC cell lines induced polarization of macrophages toward the M2 phenotype. Coculture of macrophages with cancer cells significantly induced activation of signal transducers and activators of transcription‐3 (Stat3) in the cancer cells. Direct coculture of RCC cells with macrophages led to stronger activation of Stat3 in the cancer cells than did indirect coculture using Transwell chamber dishes. Because RCC cells expressed membrane‐type macrophage colony‐stimulating factor (mM‐CSF) on the cell surface, we suggested that this mM‐CSF plays an important role in direct cell–cell interactions. Stat3 activation in cancer cells that was induced by coculture with macrophages was suppressed by downregulation of the M‐CSF receptor (M‐CSFR) in macrophages and by an inhibitor of M‐CSFR. In conclusion, investigation of CD163+ tumor‐associated macrophages would be useful for assessment of the clinical prognosis of patients with ccRCC. Cell–cell interactions mediated by mM‐CSF and M‐CSFR binding could contribute to cancer cell activation. (Cancer Sci 2011; 102: 1424–1431)

[1]  S. Okada,et al.  IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation , 2010, Cell Death and Differentiation.

[2]  H. Baba,et al.  Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma , 2010, Cancer science.

[3]  Kelly J. Morris,et al.  Brief Report Results and Discussion , 2022 .

[4]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[5]  K. Ohshima,et al.  Ratio of M2 macrophage expression is closely associated with poor prognosis for Angioimmunoblastic T‐cell lymphoma (AITL) , 2010, Pathology international.

[6]  Jeffrey Wyckoff,et al.  Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. , 2009, Cancer research.

[7]  P. Allavena,et al.  Tumor‐associated macrophages (TAM) as major players of the cancer‐related inflammation , 2009, Journal of leukocyte biology.

[8]  Michael L. Wang,et al.  Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. , 2009, Blood.

[9]  Jia-Lin Yang,et al.  Expression of M-CSF and CSF-1R is correlated with histological grade in soft tissue tumors. , 2009, Anticancer research.

[10]  T. Shinka,et al.  Angiogenesis in renal cell carcinoma: The role of tumor‐associated macrophages , 2009, International journal of urology : official journal of the Japanese Urological Association.

[11]  H. Møller,et al.  Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Andrew H. Beck,et al.  Tumorigenesis and Neoplastic Progression Coordinate Expression of Colony-Stimulating Factor-1 and Colony-Stimulating Factor-1-Related Proteins Is Associated with Poor Prognosis in Gynecological and Nongynecological Leiomyosarcoma , 2009 .

[13]  T. Lawrence,et al.  Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. , 2009, Blood.

[14]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[15]  R. Figlin,et al.  Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. , 2009, Cancer research.

[16]  B. Rini,et al.  Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients , 2009, Clinical Cancer Research.

[17]  M. Myers,et al.  Macrophage colony stimulating factor: not just for macrophages anymore! A gateway into complex biologies. , 2008, International immunopharmacology.

[18]  J. Pollard,et al.  Macrophages define the invasive microenvironment in breast cancer , 2008, Journal of leukocyte biology.

[19]  J. Kuratsu,et al.  Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas , 2008, The Journal of pathology.

[20]  P. Allavena,et al.  Cancer related inflammation: the macrophage connection. , 2008, Cancer letters.

[21]  Dirk Nagorsen,et al.  Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival , 2007, Journal of Translational Medicine.

[22]  Jung Hun Song,et al.  An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. , 2006, The Journal of clinical endocrinology and metabolism.

[23]  N. Araki,et al.  AM-3K, an Anti-macrophage Antibody, Recognizes CD163, a Molecule Associated with an Anti-inflammatory Macrophage Phenotype , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[24]  S. Gordon,et al.  Ovarian Cancer Cells Polarize Macrophages Toward A Tumor-Associated Phenotype1 , 2006, The Journal of Immunology.

[25]  Alberto Mantovani,et al.  Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. , 2006, European journal of cancer.

[26]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[27]  K. Ohba,et al.  Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. , 2005, The Journal of urology.

[28]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[29]  K. Sugimura,et al.  Effects of tumor necrosis factor α in renal cell carcinoma , 2003 .

[30]  K. Sugimura,et al.  Role of tumor-associated macrophages in renal cell carcinoma. , 2003, Oncology reports.

[31]  N. Troiano,et al.  The cell surface form of colony-stimulating factor-1 is biologically active in bone in vivo. , 2003, Endocrinology.

[32]  D. Mosser,et al.  The many faces of macrophage activation , 2003, Journal of leukocyte biology.

[33]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[34]  Toru Watanabe,et al.  Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma. , 2002, Anticancer research.

[35]  S. Horvath,et al.  Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Fiorentini,et al.  Epithelial cells and expression of the phagocytic marker CD68: scavenging of apoptotic bodies following Rho activation. , 2002, Toxicology in vitro : an international journal published in association with BIBRA.

[37]  M. Oya,et al.  Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome. , 2002, The Journal of urology.

[38]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[39]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[40]  F. Beuvon,et al.  Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. , 1994, Journal of the National Cancer Institute.

[41]  C. W. Rettenmier,et al.  Direct stimulation of cells expressing receptors for macrophage colony-stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1. , 1990, Blood.

[42]  T. Lawrence,et al.  Investigating macrophage and malignant cell interactions in vitro. , 2009, Methods in molecular biology.

[43]  Hua Yu,et al.  Tumour immunology: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment , 2007, Nature Reviews Immunology.

[44]  A. Marx,et al.  World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs , 2004 .

[45]  S. Gordon.  Alternative activation of macrophages , 2003, Nature Reviews Immunology.

[46]  K. Sugimura,et al.  Effects of tumor necrosis factor alpha in renal cell carcinoma. , 2003, Oncology reports.