Cancer and Metastasis Reviews

, Volume 28, Issue 1–2, pp 177–183 | Cite as

Tumor stroma derived biomarkers in cancer

  • Malin Sund
  • Raghu KalluriEmail author


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.


Cancer Biomarker Stroma Collagen 



This study was partially funded by a research grant from NIH DK 55001 (RK), DK62987 (RK), AA13913, DK61688, CA125550, and research funds from the Beth Israel Deaconess Medical Center for the Division of Matrix Biology. MS was funded by the Swedish Society for Medical Research (SSMF) and the Swedish Society for Medicine.


  1. 1.
    Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature Reviews. Cancer, 6, 392–401.PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman, J., & Kalluri, R. (2004). Cancer without disease. Nature, 427, 787.PubMedCrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Polyak, K. (2007). Breast cancer: origins and evolution. Journal Clinical Investigation, 117, 3155–3163.CrossRefGoogle Scholar
  5. 5.
    Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407, 249–257.PubMedCrossRefGoogle Scholar
  6. 6.
    Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine, 1, 27–31.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Riethdorf, S., Wikman, H., & Pantel, K. (2008). Review: Biological relevance of disseminated tumor cells in cancer patients. International Journal of Cancer, 123, 1991–2006.CrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 12.
    Tammela, T., Enholm, B., Alitalo, K., & Paavonen, K. (2005). The biology of vascular endothelial growth factors. Cardiovascular Research, 65, 550–563.PubMedCrossRefGoogle Scholar
  13. 13.
    Kalluri, R. (2003). Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Reviews. Cancer, 3, 422–433.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.Google Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta, G. P., & Massague, J. (2006). Cancer metastasis: building a framework. Cell, 127, 679–695.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3, 453–458.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Naumov, G. N., Folkman, J., & Straume, O. (2008). Tumor dormancy due to failure of angiogenesis: role of the microenvironment. Clinical & Experimental Metastasis.Google Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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.Google Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 55.
    Kuroi, K., & Toi, M. (2001). Circulating angiogenesis regulators in cancer patients. International Journal of Biological Markers, 16, 5–26.PubMedGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division for Matrix Biology CLS 11087Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  2. 2.Department of SurgeryUmea UniversityUmeaSweden

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