Controversial insights for lymphangiogenesis in breast cancer

Fernando C. Schmitt, Pathologist,

Other Contributors:

August 18, 2004

Dear Editor

Recently, we read with the interest the paper Lack of lymphangiogenesis during breast carcinogenesis from Vleugel et al. (J Clin Pathol.2004; 57: 746-751) [1]. These authors investigated the role of lymphangiogenesis in breast carcinogenesis. Whist the resident lymphatics and/or new tumour-induced lymphatic vessels are collapsed by the intra- tumoral pressure, or if they do facilitate the neoplastic spread are crucial questions to the understanding the biological behaviour of cancer metastasis pathways and to elaborate therapeutics targets for the new generation of chemotherapies [2].

Padera et al. demonstrated that the mass of malignant cells are able to compress the intra-tumoral lymphatic vessels [3]. These authors have hypothesised that the tumoral compression harm the lymphatic activity in intra-tumoral field, deforming and inducing damages in the lymphatic structures what seriously limits the identification of lymphatics.

The paper of Vleugel et al. [1] investigated two alleged hypothesis that closely embrace the intra-tumour absence of lymphatics: the collapse of lymphatic vessels or the lack of lymphangiogenesis in breast cancer. These authors used LYVE-1 to discriminate lymphatic vessels due to its presumed specificity to recognize lymphatics, and CD31 for the blood vessels. LYVE-1, a hyaluronan receptor expressed during the lymphatic vessels development is not exclusively expressed by lymphatics. However, in spite of conflicting results, LYVE-1 is considered a classical marker of lymphatic vessels [2]. Vleugel et al. [1] showed that both blood vessel density (BVD) and lymph vessel density (LVD) were similar among the normal and non-neoplastic proliferative (hyperplastic) breast tissue. Additionally, ductal carcinoma in situ (DCIS) has demonstrated increased BVD but not LVD. As mentioned by the authors, this is an important point to be considered, in view of the fact that no significant increased pressure is expected in DCIS. The authors also found an inverse correlation between LVD and the size of DCIS, probably due to the replacement of the stroma by the neoplastic cells. This progressive absence of lymph vessels seems to be the reason of the lacking of lymphangiogenesis in breast cancer. In most of breast invasive carcinomas studied, lymphatic vessels were not demonstrated, suggesting that the complete destructive growth pattern in invasive carcinoma induce the formation of a new stroma without lymphatics that replace the original destroyed stroma.

Recently, we studied lymphangiogenesis in a series of in situ and invasive ductal carcinomas, using VEGFR 3 as a marker. In accordance with the results reported by Vleugel et al.[1] we also did not observed increasing of lymphatic vessels surrounding ducts involved by DCIS. In invasive carcinomas we observed mainly at periphery of the tumour some small distorted vessels faintly decorated by VEGFR 3. We did not find any relationship between the number of lymphatic vessels and some clinical-pathological parameters of aggressiveness in breast cancer such as: tumour size, grading and presence of lymph node metastasis. These findings reinforce the idea that lymphangiogenesis can not be important for breast carcinogenesis and also for breast cancer progression. In spite of experimental models had demonstrated that lymphangiogenesis can promote metastasis, this is not so evident in human tumours. The tangible evidences seriously indicate that the breast cancer spread do not depends on the intra-tumoral lymphatic vessels, but maybe via pre-existing lymphatics [4,5]. Moreover, new insights suggesting the existence of a potential interaction between the tumour and the lymphatic vessels promoted by Hyaluronan expression introducing novel likely mechanisms to the metastatic spread by the lymphatics6. Another important point raised in our study was the role of VEGFR-3 in lymphangiogenesis. In our cases we also detected VEGFR-3 expression in some intra-tumoural blood vessels. Recently, Scavelli et al. [6] call the attention for the cross-talking between blood and lymphatic vessels in neoplastic conditions. Understandingly, the blood vessels marked by the VEGFR-3 can expose the pivotal action of VEGFR-3 in angiogenesis during the development, in same way reproducible under carcinogenesis scenario. However, one of the most outstanding findings in our study was the detection of VEGFR-3 expression in breast myoepithelial cells. Although expression of VEGFR-1 and VEGFR-2 had been previously described in epithelial cells, including breast malignant cells [7], as far as we know it is the first time that VEGFR-3 expression was described in breast myoepithelial cells.

In conclusion, the paper published by Vleugel et al. [1] provides new and exciting evidences of the role of new vasculature, lymphatic and blood vessels, in the breast carcinogenesis. Provide also arguments to be explored concerning the relation of molecular expression of LYVE-1 and other related-lymphangiogenic markers in lymphatic tumour-related vessels during the metastatic spread. Comprehensive studies with lymphatic markers are still required to address the mechanism of tumour behaviour and metastatic potential. The model explored by the authors should be reproduced using other markers for lymphatics and in other tumours to confirm if the lack of lymphangiogenesis in breast carcinogenesis can be extrapolate or not to others malignancies.

Adhemar Longatto Filho, PhD, PMIAC; Life and Health Science Research Institute, School of Health Sciences, University of Minho, Braga, Portugal Fernando C. Schmitt, M.D., PhD, MIAC. IPATIMUP and Medical Faculty, Porto University, Porto, Portugal e-mail: fernando.schmitt@ipatimup.pt

Address for correspondence: Fernando C. Schmitt, M.D., Ph.D, M.I.A.C. IPATIMUP Rua Roberto Frias s/n 4200 Porto Portugal Phone: 351 22 557 0700 FAX: 351 22 557 0799 e-mail: fschmitt@ipatimup.pt

Adhemar Longatto Filho is currently postdoctoral fellowship at University of Minho, supported by a FCT grant (SFRH/BPD/14616/2003)

References

(1) Vleugel MM, Bos R, van der Groep P, et al. Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol.2004; 57: 746-751

(2) Reis-Filho JS, Schmitt FC.. Lymphangiogenesis in tumours: what do we know? Microsc Res Tech 2003; 60: 171-180.

(3) Padera TP, Stoll BR, Tooderman JB, Capen D, Di Tommaso E, Jain RK. Cancer cells compress intratumour vessels. Nature 2004; 427: 695.

(4) Williams CSM, Leek RD, Robson AL et al. Absence of lymphangiogenesis and intratumoral lymph vessels in human metastatic breast cancer. J Pathol 2003; 200: 195-206.

(5) Jackson DG. The lymphatics revisited. New perspectives from the hyaluronan receptor LYVE-1. Trens Cardiovasc 2003; 13: 1-7.

(6) Scavelli C, Weber E, Aglianò M et al. Lymphatics at the croosroads of angiogenesis and lymphangiogenesis. J Anat 2004; 204: 433-449.

(7) Dales JP, Garcia S, Bonnier P, Duffaud F et al. Prognostic significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma. Ann Pathol 2003; 23: 297-305.

Conflict of Interest

None declared