Received date: December 15, 2011; Accepted date: December 16, 2011; Published date: December 17, 2011
Citation: Qian CN, Williams BO (2011) The Induction of High Endothelial Venule Remodeling by Primary Tumors does not Correlate to the Metastatic Capability of Tumor Cells. J Blood Lymph 1:e102. doi: 10.4172/2165-7831.1000e102
Copyright: © 2011 Qian CN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The metastasis of cancer cells to the draining lymph nodes isusually the initial step in systemic spreading of cancer and is the mostimportant unfavorable prognostic factor in many types of carcinoma[1-5]. The molecular mechanisms inside the lymph node favorable for survival and further spreading of cancer cells remain unclear.
There is a specific type of blood vessel called the high endothelialvenule (HEV) inside the lymph node. Under normal conditions, HEVsproduce a specific marker protein, peripheral node addressin (PNAd),which is a ligand that is recognized by the homing receptor L-selectinexpressed in the cellular membrane of naïve lymphocytes [6-8]. Theinteraction between PNAd and L-selectin results in the extravasationof lymphocytes from the circulation into the lymphoid tissue. HEVsseldom harbor red blood cells under normal conditions, instead beingfocused on immune response. However, in cancer, HEVs in the draininglymph node can be remodeled under the influence of the primarytumor, resulting in dramatic dilation of the vessel lumen, significantflattening of the endothelium, and the appearance of red blood cellsin the lumen [ 9-10]. Importantly, the remodeling procedure caneven precede the arrival of metastatic cancer cells in the lymph node.Further, remodeled HEVs can integrate into the tumor vasculature aftermetastatic cancer cells colonize in the lymph node . The remodeledand integrated HEVs lose PNAd and carry numerous red blood cells,suggesting a functional shift from immune response to blood flow thatsupports the survival and growth of the secondary tumor in the node[9-10]. The remodeled HEVs in the lymph node can become “mothervessels” of the secondary tumor [9-10], but little is known about how this occurs molecularly.
In a recent article by Farnsworth and colleagues , bonemorphogenetic protein-4 (BMP-4) was found to be expressed in normalHEV, and loss of BMP-4 correlated to more dramatic remodeling ofHEVs in the tumor-draining lymph node. This is the first identifiedmolecule with a role in tumor-induced HEV remodeling, and the evidence is strong and convincing.
The authors also suggest a link between HEV remodeling andthe metastatic capability of the primary tumor cancer cells , butthe evidence is not as robust. First, the non-metastatic control in thisstudy was the 293 EBNA-1 cell line. This is not a cancer cell line, but ahuman embryonic kidney line transfected with the EBNA-1 gene for immortalization . Therefore, the absence of HEV remodeling in the lymph node of the mice carrying a 293 EBNA-1 xenograft may not be a generalizable phenomenon associated with a non-metastatic tumor. Second, the difference in the HEV lumen area (an enlarged lumen being one of the indications of HEV remodeling) between lymph nodes associated with either nonmetastatic or/and metastatic tumors shown in Figure 4B is not observed in Figure 5C, in which the lumen areas of both types of lymph nodes were not statistically different .
In our previous study , we reported that HEV remodeling canbe induced by primary tumors formed by high-metastatic as well aslow-metastatic cellular clones, suggesting that HEV remodeling is not correlated with the metastatic ability of the cells.
In a transgenic mouse model of prostate tumor induced byinactivation of the Apc gene in the prostate epithelium via the CreloxPsystem, benign prostate tumors without metastatic ability can besuccessfully induced . In the mice bearing such benign tumors,remodeling of HEV in the sacral lymph node is evident, confirmingthat benign tumor can also induce HEV remodeling in the draining lymph nodes.
Collectively, both benign and malignant tumors, with either high orlow metastatic character, can induce HEV remodeling in the draininglymph node. Therefore, HEV remodeling cannot be regarded as one of the aggressive characteristics of the primary tumor.
However, the integration of remodeled HEVs into the tumor vasculature could have an important role in promoting the further spread of the cancer cells. Squamous cell carcinoma cells have been found to preferentially attach to HEV , suggesting that a downstream metastatic event could be promoted by the integrated HEV in the secondary tumor vasculature. Obviously, more direct evidence is needed to support the hypothesis that HEV remodeling and integration into tumor vasculature are the main reasons for the increased distant metastasis rate of cancer cells after their initial spread to the draining lymph node.
In conclusion, although HEV remodeling seems important to thesurvival and growth of secondary tumors in the lymph nodes, it doesnot unambiguously correlate with the metastatic ability of the primarytumor cells. More efforts are warranted to clarify the role of remodeledHEV for the further spreading of cancer cells from the involved lymph node.
This work was partially supported by grant from the State Key Program ofNational Natural Science Foundation of China (Grant No. 81030043). We thank David Nadziejka, Grand Rapids, Michigan, for critical reading of the manuscript.
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