Current Science

Open Access Open Access  Restricted Access Subscription Access

Intratumoural and Peritumoural Lymphangiogenesis in Canine Mammary Tumour Linked to Tumour Spread and Poor Survival


Affiliations
1 Department of Veterinary Pathology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004, India
2 Department of Veterinary Microbiology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004,, India
 

Canine mammary tumour (CMT) is an excellent, naturally occurring animal model for human breast cancer. Most research, so far, has focused on angiogenesis as a mode of tumour invasion and metastasis, but the role of lymphangiogenesis in mammary tumours is scarcely documented. The present study was conducted on 45 cases of CMT and the extent of lymphangiogenesis, demonstrated as intratumoural vessel density (IVD) and peritumoural vessel density (PVD) was determined by immunohistochemical staining with lymphatic markers, viz. podoplanin, LYVE-1, PROX 1 and VEGFR-3. The highest vessel density in intratumoural area was recorded with VEGFR-3 (35.94 ± 3.45), followed by podoplanin (31.95 ± 2.77), LYVE-1 (11.11 ± 2.20) and PROX 1 (7.62 ± 1.11). In peritumoural areas, the vessel density was highest with podoplanin (11.48 ± 1.32), followed by VEGFR-3 (7.69 ± 0.51), LYVE-1 (5.19 ± 0.96) and PROX 1 (3.48 ± 0.48). The lymphatics in intratumoural areas were small, thin and collapsed, whereas the peritumoural lymphatics were large and conspicuous. Overall survival was less in patients with high lymphatic density in peritumoural areas for podoplanin, and with high vessel density in intratumoural areas for VEGFR-3. The survival was also low in cases with lymphatic tumour emboli. It was concluded that both intratumoural and peritumoural lymphangiogenesis seemed to play significant role in tumour invasion and spread rather than peritumoural lymphatics. Moreover, the podoplanin and PROX 1 were found to be more specific markers of lymphangiogenesis.

Keywords

Canine Mammary Tumour, Immunohistochemistry, Kaplan Meier Survival Analysis, Lymphangiogenesis.
User
Notifications
Font Size

  • Stewart, B. and Kleihues, P., International agency on research for cancer. In World Health Organization World Cancer Report. IARC Press, Lyon, 2003.

  • Raica, M., Jung, I., Cimpean, A. M., Suciu, C. and Muresan, A. M., From conventional pathologic diagnosis to the molecular classification of breast carcinoma: are we ready for the change? Rom. J. Morphol. Embryol., 2009, 50, 5-13.

  • Khanna, C. et al., The dog as a cancer model. Nat. Biotechnol., 2006, 24, 1065-1066.

  • Mulas, J. M. and Reymundo, C., Animal models of human breast carcinoma: canine and feline neoplasms. Clin. Transl. Oncol., 2000, 2, 274-281.

  • Gupta, K. et al., Epidemiological studies on canine mammary tumour and its relevance for breast cancer studies. IOSR J. Pharm., 2012, 2, 322-333.

  • Misdorp, W., Tumours of the mammary gland. Tumours in Domestic Animals (ed. Meuten, D. J.), Iowa State Press, Ames, 2002; 4th edn, pp. 575-606.

  • Rutteman, G. R., Withrow, S. J. and MacEwen, E. G., Tumors of the mammary gland. In Small Animal Clinical Oncology (eds Withrow, S. J. and MacEwen, E. G.), WB Saunders, Philadelphia, 2001, pp. 455-477.

  • Yan, G., Zhou, X. Y., Cai, S. J., Zhang, G. H., Peng, J. J. and Xiang. D., Lymphangiogenic and angiogenic microvessel density in human primary sporadic colorectal carcinoma. World J. Gastroenterol., 2008, 14, 101-107.

  • Cunnick, G. H. et al., Lymphangiogenesis and lymph node metastasis in breast cancer. Mol. Cancer, 2008, 7, 23.

  • Sarli, G., Sassi, F., Brunetti, B., Rizzo, A., Diracca, L. and Benazzi, C., Lymphatic vessels assessment in feline mammary tumours. BMC Cancer, 2007, 7, 7.

  • Bancroft, J. D. and Gamble, M., Theory and Practice of Histological Techniques, Churchill Livingstone, Elsevier, China, 2008.

  • Yuan, P. et al., Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer, 2006, 107, 563-569.

  • Wang, X. L., Fang, J. P., Tang, R. Y. and Chen, X. M., Different significance between intratumoural and peritumoural lymphatic vessel density in gastric cancer: a retrospective study of 123 cases. BMC Cancer, 2010, 10, 299.

  • Zhao, Y. C. et al., Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients. World J. Surg. Oncol., 2012, 10, 165.

  • Weninger, W. et al., Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumour cells. Lab. Invest., 1999, 79, 243-251.

  • Carvalho, F. M., Zaganelli, F. L., Almeida, B. G. L., Goes, J. C. S., Baracat, E. C. and Carvalho, J. P., Prognostic value of podoplanin expression in intratumoural stroma and neoplastic cells of uterine cervical carcinomas. Clinics, 2010, 65, 1279-1283.

  • Stacker, S. A., Achen, M. G., Jussila, L., Baldwin, M. E. and Alitalo, K., Lymphangiogenesis and cancer metastasis. Nat. Rev. Cancer, 2002, 2, 573-583.

  • Gu, Y., Qi, X. and Guo, S., Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin. Exp. Metastasis, 2008, 25, 717-725.

  • Banerji, S. et al., LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph- specific receptor for hyaluronan. J. Cell Biol., 1999, 144, 789-801.

  • Pflicke, H. and Sixt, M., Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J. Exp. Med., 2009, 206, 2925-2935.

  • Nicosia, R. F., Angiogenesis and the formation of lymphatic-like channels in cultures of thoracic duct. In Vitro Cell. Dev. Biol., 1987, 23, 167-174.

  • Akishima, Y. et al., Immunohistochemical detection of human small lymphatic vessels under normal and pathological conditions using the LYVE- 1 antibody. Virchows Arch., 2004, 44, 153-157.

  • Auwera, I. V. et al., Increased angiogenesis and lymphangiogenesis in inflammatory versus non-inflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin. Cancer Res., 2004, 10, 7965-7971.

  • Makinen, T. et al., Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J., 2001, 20, 4762-4773.

  • Wigle, J. T. and Oliver, G., PROX 1 function is required for the development of the murine lymphatic system. Cell, 1999, 98, 769-778.

  • Xu, S., PROX 1 facilitates transfected CHO cell proliferation through activation of the AKT signaling pathway. Int. J. Biomed. Sci., 2010, 6, 49-59.

  • Skog, M. et al., Expression and prognostic value of transcription factor PROX 1 in colorectal cancer. Br. J. Cancer, 2011, 105, 1346-1351.

  • Karkkainen, M. J. and Petrova, T. V., Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene, 2000, 19, 5598-5605.

  • Karkkainen, M. J. et al., Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol., 2004, 5, 74-80.

  • Botting, S. K. et al., Prognostic significance of peritumoral lymphatic vessel density and vascular endothelial growth factor receptor 3 in invasive squamous cell cervical cancer. Trans. Oncol., 2010, 3, 170-175.

  • Lo, H. W. and Hung, M. C., Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br. J. Cancer, 2006, 94, 184-188.

  • Kyzas, P. A., Geleff, S., Batistatou, A., Agnantis, N. J. and Stefanou, D., Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J. Pathol., 2005, 206, 170-177.

  • Thiele, W. and Sleeman, J. P., Tumor-induced lymphangiogenesis: a target for cancer therapy? J. Biotechnol., 2006, 124, 224-241.

  • Gombos, Z., Xu, X., Chu, C. S., Zhang, P. J. and Acs, G., Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin. Cancer Res., 2005, 11, 8364-8371.

  • He, Y., Karpanen, T. and Atialo, K., Role of lymphangiogenic factors in tumor metastasis. Biochim. Biophys. Acta, 2004, 1645, 3-12.

  • Simona, B. et al., Multiple myeloma macrophages: pivotal players in the tumor microenvironment. J. Oncol., 2013; doi: 10.1155/ 2013/183602.

  • Raposo, T. P., Pires, I., Carvalho, M. I., Prada, J., Argyle, D. J. and Queiroga, F. L., Tumour-associated macrophages are associated with vascular endothelial growth factor expression in canine mammary tumours. Vet. Comp. Oncol., 2015, 13(4), 464-474.


Abstract Views: 228

PDF Views: 70




  • Intratumoural and Peritumoural Lymphangiogenesis in Canine Mammary Tumour Linked to Tumour Spread and Poor Survival

Abstract Views: 228  |  PDF Views: 70

Authors

Parmeet Pal Singh
Department of Veterinary Pathology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004, India
Naresh Kumar Sood
Department of Veterinary Pathology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004, India
Kuldip Gupta
Department of Veterinary Pathology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004, India
Deepti Narang
Department of Veterinary Microbiology, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana 141 004,, India

Abstract


Canine mammary tumour (CMT) is an excellent, naturally occurring animal model for human breast cancer. Most research, so far, has focused on angiogenesis as a mode of tumour invasion and metastasis, but the role of lymphangiogenesis in mammary tumours is scarcely documented. The present study was conducted on 45 cases of CMT and the extent of lymphangiogenesis, demonstrated as intratumoural vessel density (IVD) and peritumoural vessel density (PVD) was determined by immunohistochemical staining with lymphatic markers, viz. podoplanin, LYVE-1, PROX 1 and VEGFR-3. The highest vessel density in intratumoural area was recorded with VEGFR-3 (35.94 ± 3.45), followed by podoplanin (31.95 ± 2.77), LYVE-1 (11.11 ± 2.20) and PROX 1 (7.62 ± 1.11). In peritumoural areas, the vessel density was highest with podoplanin (11.48 ± 1.32), followed by VEGFR-3 (7.69 ± 0.51), LYVE-1 (5.19 ± 0.96) and PROX 1 (3.48 ± 0.48). The lymphatics in intratumoural areas were small, thin and collapsed, whereas the peritumoural lymphatics were large and conspicuous. Overall survival was less in patients with high lymphatic density in peritumoural areas for podoplanin, and with high vessel density in intratumoural areas for VEGFR-3. The survival was also low in cases with lymphatic tumour emboli. It was concluded that both intratumoural and peritumoural lymphangiogenesis seemed to play significant role in tumour invasion and spread rather than peritumoural lymphatics. Moreover, the podoplanin and PROX 1 were found to be more specific markers of lymphangiogenesis.

Keywords


Canine Mammary Tumour, Immunohistochemistry, Kaplan Meier Survival Analysis, Lymphangiogenesis.

References





DOI: https://doi.org/10.18520/cs%2Fv115%2Fi7%2F1312-1319