See related article on page 2100
Tumor-associated macrophages (TAMs) orchestrate various aspects of cancer progression, including the promotion of tumor angiogenesis independent of vascular endothelial growth factor (VEGF) signaling. Thus, macrophage-targeted therapy, such as colony-stimulating factor 1 (CSF1) blockade, represents a promising anticancer strategy. However, the role of macrophages varies according to the type of cancer. Therefore, it is important to know whether and to what degree specific tumors depend on macrophage-driven angiogenesis. In this issue of The American Journal of Pathology, Espinosa et al
1
investigated 149 cases of leiomyosarcoma (LMS), a malignant neoplasm of smooth muscle. They report that the number of macrophages and the levels of CSF1 expression highly correlated with microvessel density and poor prognosis in nongynecological LMS cases. Notably, the microvessel density of these tumors showed either no correlation or negative correlation to VEGF-A. These data provide a rationale for CSF1 targeted therapies in nongynecological LMS, validating the use of CSF1 inhibitors, rather than VEGF blockers, for suppression of tumor angiogenesis in certain types of tumors.Macrophages and Angiogenesis
CSF1 mediates the differentiation of monocytes into macrophages. Macrophages function in both nonspecific (innate immunity) and specific (adaptive immunity) defense mechanisms in vertebrate animals through phagocytosis of cellular debris and pathogens. Aside from its well-known role in the immune system, macrophage roles in angiogenesis have also garnered attention. Recent genetic evidence demonstrates that macrophages promote angiogenic branching
2
and anastomosis3
in physiological settings. Macrophages stimulate vessel sprouting in aortic ring cultures by secreting a soluble factor other than VEGF-A, rather than by direct contact with endothelial cells.4
These data suggest that macrophages promote angiogenesis independently of the VEGF signaling.Tumor Angiogenesis and VEGF
The tumor microenvironment is prominently visible on histological examination and consists of a complex mixture of cell types. Moses Judah Folkman,
5
well-known as the father of tumor angiogenesis, first proposed the importance of tumor vascularity. He declared that if a tumor could be stopped from growing its own blood supply, it would wither and die. Since then, various studies have led to the discovery of a growing number of anti-angiogenic molecules limiting tumor angiogenesis. Among them, VEGF blockers are one of the most accepted anti-angiogenic treatments because tumor angiogenesis mostly depends on VEGF. Several VEGF blockers have already been approved for clinical use in cancer, and multiple lines of studies6
, 7
have reported significant therapeutic efficacy; however, a fraction of patients are refractory or acquire resistance to VEGF inhibitors.8
In these patients, compensation by other pro-angiogenic mechanisms may contribute to poor responsiveness to VEGF blockade. The extent of refractoriness varies from one cancer to another and differs among various types of VEGF blockers. Understanding the molecular basis of these cancer type–dependent resistance mechanisms against VEGF blockade offers opportunities to improve anti-angiogenic treatment.Macrophages: Cellular Hubs Essential for Tumor Angiogenesis
During cancer progression, TAMs play diverse and complicated roles.
9
TAMs orchestrate various aspects of cancer progression, including diverting and skewing adaptive responses, cell growth, matrix deposition and remodeling, and constructing a metastatic niche. The promotion of tumor angiogenesis is one of the most important roles of TAMs. Pollard and colleagues10
first established the role of TAMs in the angiogenic switch, which is identified as the formation of a high-density vessel network that promotes the tumors into a malignant state. Recently, myeloid cell/macrophage-driven angiogenesis associated with refractoriness or resistance to VEGF blockade.2
, 11
However, this significance of macrophage-driven angiogenesis highly varies according to the type of cancer. Therefore, it is important to know how specific tumors depend on macrophage-driven angiogenesis.LMS and Macrophages
LMS, a malignant neoplasm of smooth muscle, is a relatively rare form of cancer, composing between 5% and 10% of soft tissue sarcomas.
12
LMS is resistant to treatment, with little responsiveness to chemotherapy or radiation. The best prognosis is obtained when LMS is surgically removed, including a wide margin of normal tissues, at an early stage, while the tumor is small and still in situ.13
LMS predominantly occurs in the female genital tract (gynecological LMS) or deep soft tissues (nongynecological LMS). van de Rijn and colleagues14
have investigated the tumor microenvironment of LMS, finding that more TAMs in nongynecological LMS indicate a poorer prognosis. Moreover, they found that the expression of CSF1, a major differentiation and survival factor for macrophages, positively correlates with poor prognosis in both gynecological and nongynecological LMS.15
However, given that the functions of TAMs are diverse and complicated, as previously described, it is unclear how TAMs and CSF1 contribute to the poor clinical outcomes of LMS.- Espinosa I.
- Beck A.H.
- Lee C.H.
- Zhu S.
- Montgomery K.D.
- Marinelli R.J.
- Ganjoo K.N.
- Nielsen T.O.
- Gilks C.B.
- West R.B.
- van de Rijn M.
Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1-related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma.
Am J Pathol. 2009; 174: 2347-2356
Macrophage-Driven Angiogenesis in LMS
In their article, Espinosa et al
1
explored the link between TAMs, CSF1, and poor prognosis in LMS. They quantified microvessel density, CSF1 expression, and patient prognosis in 149 LMS cases. The data show that high microvessel density in nongynecological, but not gynecological, LMS cases significantly predicts poor patient outcome. Furthermore, most cases presenting high microvessel density were CSF1 positive; when combining high microvessel density with CSF1 expression, an even stronger prognostic correlation with patient outcome was obtained. More important, they found either a nonsignificant or a negative correlation between microvessel density and VEGF-A expression. In xenograft studies using immune-deficient mice, CSF1 expression and TAM recruitment remained consistent between primary tumors and those grown as xenografts in mice, supporting the stability of these features as intrinsic to LMS tumors.Future Perspective
Espinosa et al
1
demonstrated that microvessel density predicts the outcome of nongynecological, but not gynecological, LMS, which is in stark contrast to what is known for soft tissue sarcomas.16
Microvessel density correlates with important clinical features in patients with sarcomas, ranging from soft tissue to bone sarcomas. Identifying the diagnostic subtypes of sarcomas, as in nongynecological and gynecological LMS, is essential. Although these data provide a rationale for CSF1 targeted therapies in nongynecological LMS, further functional studies, such as CSF1 inhibition in the LMS tumor model, may aid in using this strategy in clinical settings. It is also important to know whether the CSF1 receptor is expressed in tumor cells of LMS and in macrophages. A recent study17
showed that, in acute myeloid leukemia, the expression of the CSF1 receptor is increased in leukemia-initiating cells, which could be a therapeutic target for leukemia eradication. Finally, viewing these results broadly, the presented data for LMS may validate the use of CSF1 inhibitors, rather than VEGF blockers, for the suppression of tumor angiogenesis in other types of tumors.References
- CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis.Am J Pathol. 2011; 179: 2100-2107
- M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis.J Exp Med. 2009; 206: 1089-1102
- Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.Blood. 2010; 116: 829-840
- A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures.PLoS One. 2011; 6: e15846
- Tumor angiogenesis: therapeutic implications.N Engl J Med. 1971; 285: 1182-1186
- VEGF-A: a critical regulator of blood vessel growth.Eur Cytokine Netw. 2009; 20: 158-163
- Molecular mechanisms and clinical applications of angiogenesis.Nature. 2011; 473: 298-307
- Modes of resistance to anti-angiogenic therapy.Nature Rev Cancer. 2008; 8: 592-603
- Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51
- Macrophages regulate the angiogenic switch in a mouse model of breast cancer.Cancer Res. 2006; 66: 11238-11246
- Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis.Curr Opin Hematol. 2010; 17: 219-224
- Soft tissue leiomyosarcoma: a population-based epidemiologic and prognostic study of 48 patients, including cellular DNA content.Cancer. 1992; 70: 114
- Diagnosis and management of primary pulmonary leiomyosarcoma.J Am Osteopath Assoc. 2010; 110: 244-246
- Prognostic significance of macrophage infiltration in leiomyosarcomas.Clin Cancer Res. 2008; 14: 1423-1430
- Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1-related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma.Am J Pathol. 2009; 174: 2347-2356
- Markers of angiogenesis and clinical features in patients with sarcoma.Cancer. 2007; 109: 813-819
- PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2.Nat Med. 2010; 16: 580-585
Article info
Publication history
Published online: August 12, 2011
Accepted:
July 6,
2011
Footnotes
Supported by Grants-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a research grant from Takeda Science Foundation, and the Keio Kanrinmaru Project.
CME Disclosure: None of the authors disclosed any relevant financial relationships.
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© 2011 American Society for Investigative Pathology. Published by Elsevier Inc.
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- CSF1 Expression in Nongynecological Leiomyosarcoma Is Associated with Increased Tumor AngiogenesisThe American Journal of PathologyVol. 179Issue 4
- PreviewLeiomyosarcoma (LMS) is a malignant tumor of smooth muscle cells for which few effective therapies exist. A subset of LMS cases express macrophage colony-stimulating factor (CSF1) and the resultant tumor-associated macrophage (TAM) infiltration predicts poor clinical outcome. Further, TAMs have been shown to increase tumor angiogenesis. Here, we analyzed 149 LMS cases by immunohistochemistry for vascular marker CD34 and show that high microvessel density (MVD) in nongynecological LMS cases significantly predicts poor patient outcome.
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