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Published in:

01-06-2009

Tumor stroma derived biomarkers in cancer

Authors: Malin Sund, Raghu Kalluri

Published in: Cancer and Metastasis Reviews | Issue 1-2/2009

Abstract

In recent years the importance of the tumor stroma for the development, promotion and invasion of cancer is becoming increasingly clear. Besides a malignantly transformed cancer cell, tumors also contains many other cell types, including endothelial cells, fibroblasts and cells of the immune system. These cells together with the cancer cells produce the sum extracellular matrix (ECM) of the tumor. The ECM and the non-malignant cells of the tumor are defined as the “tumor stroma”. Just as the malignant cell itself can be the source of substances that can be used as biomarkers of cancer, the tumor stroma contains factors that potentially can be used as biomarkers when treating patients with cancer. In this review we will discuss the role of the tumor stroma as a source of new cancer biomarkers. This concept highlights a novel view of cancer and treats them as organized organs. Additionally, this further stresses the importance of including factors related to the tumor stroma into the diagnostic and therapeutic equation of cancer.

Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature Reviews. Cancer, 6, 392–401.PubMedCrossRef

Folkman, J., & Kalluri, R. (2004). Cancer without disease. Nature, 427, 787.PubMedCrossRef

Hu, M., Yao, J., Cai, L., Bachman, K. E., van den Brule, F., Velculescu, V., et al. (2005). Distinct epigenetic changes in the stromal cells of breast cancers. Nature Genetics, 37, 899–905.PubMedCrossRef

Polyak, K. (2007). Breast cancer: origins and evolution. Journal Clinical Investigation, 117, 3155–3163.CrossRef

Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407, 249–257.PubMedCrossRef

Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine, 1, 27–31.PubMedCrossRef

Finak, G., Bertos, N., Pepin, F., Sadekova, S., Souleimanova, M., Zhao, H., et al. (2008). Stromal gene expression predicts clinical outcome in breast cancer. Nature Medicine, 14, 518–527.PubMedCrossRef

Riethdorf, S., Wikman, H., & Pantel, K. (2008). Review: Biological relevance of disseminated tumor cells in cancer patients. International Journal of Cancer, 123, 1991–2006.CrossRef

O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997). Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277–285.PubMedCrossRef

10.

Saarela, J., Rehn, M., Oikarinen, A., Autio-Harmainen, H., & Pihlajaniemi, T. (1998). The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. American Journal of Pathology, 153, 611–626.PubMed

11.

Hutchings, H., Ortega, N., & Plouet, J. (2003). Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. FASEB Journal, 17, 1520–1522.PubMed

12.

Tammela, T., Enholm, B., Alitalo, K., & Paavonen, K. (2005). The biology of vascular endothelial growth factors. Cardiovascular Research, 65, 550–563.PubMedCrossRef

13.

Kalluri, R. (2003). Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Reviews. Cancer, 3, 422–433.PubMedCrossRef

14.

Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., et al. (2000). Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. Journal of Biological Chemistry, 275, 1209–1215.PubMedCrossRef

15.

Maeshima, Y., Sudhakar, A., Lively, J. C., Ueki, K., Kharbanda, S., Kahn, C. R., et al. (2002). Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science, 295, 140–143.PubMedCrossRef

16.

Mundel, T. M., Yliniemi, A. M., Maeshima, Y., Sugimoto, H., Kieran, M., & Kalluri, R. (2008). Type IV collagen alpha6 chain-derived noncollagenous domain 1 (alpha6(IV)NC1) inhibits angiogenesis and tumor growth. International Journal of Cancer, 122, 1738–1744.CrossRef

17.

Sudhakar, A., Nyberg, P., Keshamouni, V. G., Mannam, A. P., Li, J., Sugimoto, H., et al. (2005). Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin. Journal of Clinical Investigation, 115, 2801–2810.PubMedCrossRef

18.

Kunz-Schughart, L. A., & Knuechel, R. (2002). Tumor-associated fibroblasts (part I): Active stromal participants in tumor development and progression? Histology and Histopathology, 17, 599–621.PubMed

19.

Hung, K. E., Kho, A. T., Sarracino, D., Richard, L. G., Krastins, B., Forrester, S., et al. (2006). Mass spectrometry-based study of the plasma proteome in a mouse intestinal tumor model. Journal of Proteome Research, 5, 1866–1878.PubMedCrossRef

20.

Dhakal, H. P., Naume, B., Synnestvedt, M., Borgen, E., Kaaresen, R., Schlichting, E., et al. (2008). Vascularization in primary breast carcinomas: its prognostic significance and relationship with tumor cell dissemination. Clinical Cancer Research, 14, 2341–2350.PubMedCrossRef

21.

Kato, T., Kameoka, S., Kimura, T., Soga, N., Abe, Y., Nishikawa, T., et al. (2001). Angiogenesis as a predictor of long-term survival for 377 Japanese patients with breast cancer. Breast Cancer Research and Treatment, 70, 65–74.PubMedCrossRef

22.

Pinder, S. E., Ellis, I. O., Galea, M., O’Rouke, S., Blamey, R. W., & Elston, C. W. (1994). Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology, 24, 41–47.PubMedCrossRef

23.

Uzzan, B., Nicolas, P., Cucherat, M., & Perret, G. Y. (2004). Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Research, 64, 2941–2955.PubMedCrossRef

24.

Van den Eynden, G. G., Colpaert, C. G., Couvelard, A., Pezzella, F., Dirix, L. Y., Vermeulen, P. B., et al. (2007). A fibrotic focus is a prognostic factor and a surrogate marker for hypoxia and (lymph)angiogenesis in breast cancer: review of the literature and proposal on the criteria of evaluation. Histopathology, 51, 440–451.PubMedCrossRef

25.

Casey, T., Bond, J., Tighe, S., Hunter, T., Lintault, L., Patel, O., et al. (2008). Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Research and Treatment.

26.

Roepman, P., de Koning, E., van Leenen, D., de Weger, R. A., Kummer, J. A., Slootweg, P. J., et al. (2006). Dissection of a metastatic gene expression signature into distinct components. Genome Biology, 7, R117.PubMedCrossRef

27.

Gupta, G. P., & Massague, J. (2006). Cancer metastasis: building a framework. Cell, 127, 679–695.PubMedCrossRef

28.

Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews. Cancer, 2, 563–572.PubMedCrossRef

29.

Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3, 453–458.PubMedCrossRef

30.

Karnoub, A. E., Dash, A. B., Vo, A. P., Sullivan, A., Brooks, M. W., Bell, G. W., et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449, 557–563.PubMedCrossRef

31.

Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. New England Journal of Medicine, 353, 793–802.PubMedCrossRef

32.

Naumov, G. N., Folkman, J., & Straume, O. (2008). Tumor dormancy due to failure of angiogenesis: role of the microenvironment. Clinical & Experimental Metastasis.

33.

Brideau, G., Makinen, M. J., Elamaa, H., Tu, H., Nilsson, G., Alitalo, K., et al. (2007). Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Research, 67, 11528–11535.PubMedCrossRef

34.

Sudhakar, A., Sugimoto, H., Yang, C., Lively, J., Zeisberg, M., & Kalluri, R. (2003). Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proceedings of the National Academy of Sciences of the United States of America, 100, 4766–4771.PubMedCrossRef

35.

Sund, M., Hamano, Y., Sugimoto, H., Sudhakar, A., Soubasakos, M., Yerramalla, U., et al. (2005). Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proceedings of the National Academy of Sciences of the United States of America, 102, 2934–2939.PubMedCrossRef

36.

Eder Jr., J. P., Supko, J. G., Clark, J. W., Puchalski, T. A., Garcia-Carbonero, R., Ryan, D. P., et al. (2002). Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily. Journal of Clinical Oncology, 20, 3772–3784.PubMedCrossRef

37.

Herbst, R. S., Mullani, N. A., Davis, D. W., Hess, K. R., McConkey, D. J., Charnsangavej, C., et al. (2002). Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. Journal of Clinical Oncology, 20, 3804–3814.PubMedCrossRef

38.

Ling, Y., Yang, Y., Lu, N., You, Q. D., Wang, S., Gao, Y., et al. (2007). Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells. Biochemical and Biophysical Research Communications, 361, 79–84.PubMedCrossRef

39.

Lu, N., Ling, Y., Gao, Y., Chen, Y., Mu, R., Qi, Q., et al. (2008). Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells. Experimental Biology and Medicine (Maywood), 233, 1013–1020.CrossRef

40.

Sun, L., Ye, H. Y., Zhang, Y. H., Guan, Y. S., & Wu, H. (2007). Epidermal growth factor receptor antibody plus recombinant human endostatin in treatment of hepatic metastases after remnant gastric cancer resection. World Journal of Gastroenterology: WJG, 13, 6115–6118.PubMedCrossRef

41.

Hata, K., Fujiwaki, R., Nakayama, K., & Miyazaki, K. (2001). Expression of the Endostatin gene in epithelial ovarian cancer. Clinical Cancer Research, 7, 2405–2409.PubMed

42.

Musso, O., Rehn, M., Theret, N., Turlin, B., Bioulac-Sage, P., Lotrian, D., et al. (2001). Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas. Cancer Research, 61, 45–49.PubMed

43.

Ohlund, D., Ardnor, B., Oman, M., Naredi, P., & Sund, M. (2008). Expression pattern and circulating levels of endostatin in patients with pancreas cancer. International Journal of Cancer, 122, 2805–2810.CrossRef

44.

Vaananen, A., Ylipalosaari, M., Parikka, M., Kainulainen, T., Rehn, M., Heljasvaara, R., et al. (2007). Collagen XVIII modulation is altered during progression of oral dysplasia and carcinoma. Journal of Oral Pathology & Medicine, 36, 35–42.

45.

Felbor, U., Dreier, L., Bryant, R. A., Ploegh, H. L., Olsen, B. R., & Mothes, W. (2000). Secreted cathepsin L generates endostatin from collagen XVIII. EMBO Journal, 19, 1187–1194.PubMedCrossRef

46.

Heljasvaara, R., Nyberg, P., Luostarinen, J., Parikka, M., Heikkila, P., Rehn, M., et al. (2005). Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Experimental Cell Research, 307, 292–304.PubMedCrossRef

47.

Wen, W., Moses, M. A., Wiederschain, D., Arbiser, J. L., & Folkman, J. (1999). The generation of endostatin is mediated by elastase. Cancer Research, 59, 6052–6056.PubMed

48.

Italiano Jr., J. E., Richardson, J. L., Patel-Hett, S., Battinelli, E., Zaslavsky, A., Short, S., et al. (2008). Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood, 111, 1227–1233.PubMedCrossRef

49.

Bono, P., Teerenhovi, L., & Joensuu, H. (2003). Elevated serum endostatin is associated with poor outcome in patients with non-Hodgkin lymphoma. Cancer, 97, 2767–2775.PubMedCrossRef

50.

Feldman, A. L., Alexander Jr., H. R., Bartlett, D. L., Kranda, K. C., Miller, M. S., Costouros, N. G., et al. (2001a). A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases. Annals of Surgical Oncology, 8, 741–745.PubMedCrossRef

51.

Feldman, A. L., Pak, H., Yang, J. C., Alexander Jr., H. R., & Libutti, S. K. (2001b). Serum endostatin levels are elevated in patients with soft tissue sarcoma. Cancer, 91, 1525–1529.PubMedCrossRef

52.

Feldman, A. L., Alexander Jr., H. R., Yang, J. C., Linehan, W. M., Eyler, R. A., Miller, M. S., et al. (2002). Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma. Cancer, 95, 1637–1643.PubMedCrossRef

53.

Guan, K. P., Ye, H. Y., Yan, Z., Wang, Y., & Hou, S. K. (2003). Serum levels of endostatin and matrix metalloproteinase-9 associated with high stage and grade primary transitional cell carcinoma of the bladder. Urology, 61, 719–723.PubMedCrossRef

54.

Hata, K., Dhar, D. K., Kanasaki, H., Nakayama, K., Fujiwaki, R., Katabuchi, H., et al. (2003). Serum endostatin levels in patients with epithelial ovarian cancer. Anticancer Research, 23, 1907–1912.PubMed

55.

Kuroi, K., & Toi, M. (2001). Circulating angiogenesis regulators in cancer patients. International Journal of Biological Markers, 16, 5–26.PubMed

56.

Zhao, J., Yan, F., Ju, H., Tang, J., & Qin, J. (2004). Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer. Cancer Letters, 204, 87–95.PubMedCrossRef

Title: Tumor stroma derived biomarkers in cancer
Authors: Malin Sund
Raghu Kalluri
Publication date: 01-06-2009
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 1-2/2009
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-008-9175-2

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