Research Article: A longitudinal MRI study on lymph nodes histiocytosis of a xenograft cancer model

Date Published: July 13, 2017

Publisher: Public Library of Science

Author(s): María Jiménez-González, Sandra Plaza-García, Janire Arizeta, Silvia Bianchessi, César Trigueros, Torsten Reese, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0181043

Abstract

Efforts are continuously made to detect and investigate the pivotal processes and interplay between the response of sentinel lymph node and malignant cells from a primary tumor. Conversely, some frequently used tumor animal models, such as human cancer xenografts, rarely feature metastasis. Therefore, lymph node alterations are seldom assessed. We consider that studying lymph node response could contribute to the understanding of host reaction to cancer. In the present study, we explored the presence of regional lymph node alterations in parallel with tumor growth using a pancreatic tumor xenograft model which does not develop metastasis.

We established an animal cancer model by the subcutaneous inoculation of PANC-1 (a metastatic human pancreatic cancer cell line) in the left upper flank of athymic nude mice. Tumor animals, along with controls (n = 7 / group) were subjected to Magnetic Resonance Imaging (MRI) in order to follow tumor growth and brachial and axillary lymph nodes alterations over several weeks. Further histological analyses were performed at the end of the study.

The lack of metastasis as well as the pathological manifestation of the lymph node alteration in this pre-clinical model established here parallels findings in patients with sinus histiocytosis that is correlated with improved survival.

Partial Text

Several studies have tried to understand the mechanism of lymph node metastasis arising from solid tumors like breast [1, 2], pancreatic [3], cervical [4] and gastric cancer [5]. The lymph node structure harbours cell populations of the innate and adaptative immune system which, in principle, will have a capacity of tackling the metastatic spread [6, 7, 8]. In fact, lymph node activation with histiocytosis described in patients with several cancers, such as breast [9], head and neck [10] and bladder [11] was a good prognostic indicator for survival. On the contrary, lymphatic metastasis is an early event within the tumor progression that is considered a key factor in poor prognosis, especially after resection of the tumoral mass [12]. Thus, a common procedure for melanoma and breast cancer is to perform a sentinel lymph node biopsy in search for the presence of malignant cells which, in turn, may indicate the spread of cancer in other organs [13, 14, 15]. Hence, efforts were made to investigate the pivotal processes and interplay between the response of sentinel lymph node and malignant cells from the primary tumor [16].

Our T1-weighted protocol was optimised to image the tumor size only. Initial experiments were also performed with a T2-weighted sequence and the relaxation times were determined, however, and T1- and T2 values are homogeneous throughout the tumor [27]. The MR images of the tumors were homogeneous in appearance, hardly capable of distinguishing between necrotic core and tumor mass. Additional characterization of the tumor itself could be performed using diffusion weighted MRI [28, 29], dynamic contrast enhanced MRI [30] or the perfusion status could be determined using arterial spin labelling methodologies [31]. As expected, the tumor volume measured by MR was significantly lower than measured by caliper (which is also measuring the skin). Three lymph node ‘types’ could be generally identified by MRI. First, the lymph node appeared normal and was able to be visualized with an in-plane resolution of < 117 μm at 11.7 Tesla. Second, the lymph node was larger but displayed roughly a morphology similar to a normal lymph node (cortical sinus, medullar sinus and follicles). Third, the lymph node appeared swollen and bright on MR images which showed a medullary cyst within the lymph node. The cysts occupied almost the complete area from medullar sinus to paracortex, displacing follicles and cortex. Similar features have been reported in other strains [17, 19] and athymic rats [18]. The SCID mouse, which lacks complete adaptative immunity (B and T-Cells), had on average only 25% of the wild type lymph node size [19]. Paradoxically, the nude mouse, which lacks mature functional T-Cells, displayed much larger lymph nodes than the wild type. It seems that the nude strains compensate for the impaired immune system by lymph nodes hyperplasia. Interestingly, subcutaneous xenograft cancer models are commonly utilizing this athymic immunodefficient mouse. Nevertheless, despite implantation of aggressive human cancer cell line, frequently derived from patient that suffered lymphatic metastasis, an invasion to the lymph node is seldomly observed [32, 33]. The pre-clinical model described here, possesses migrating Panc-1 tumor cells to sentinel lymph nodes, without causing metastasis. The model resembles a form of sinus histiocytosis and is suitable to study important aspects of the underlying mechanisms and signalling that are responsible to stop proliferating cancer cells from building active colonies in form of lymph node metastasis. Hence, future in vivo studies could be used to identify novel imaging- or bio-markers describing the interplay of cancer-cell migration, sentinel lymph node pathophysiology and anti-metastatic effects. Lymph node activation, directed by innate immune system, could be related and/or partially imply that primary tumor cells preferentially migrate via the lymphatic system and not via the blood. It may explain why patients with resected tumors but sinus histiocytosis have a better prognosis than patients without these ‘reactive’ lymph nodes.   Source: http://doi.org/10.1371/journal.pone.0181043

 

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