Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts

Andersen, Lise Mari K.; Wegner, Catherine S.; Simonsen, Trude G.; Huang, Ruixia; Gaustad, Jon Vidar; Hauge, Anette; Galappathi, Kanthi; Rofstad, Einar K.

doi:10.18632/oncotarget.18231

Cited by 11 publications

(7 citation statements)

References 77 publications

(108 reference statements)

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“…Intramuscular transplantation was preferred to subcutaneous transplantation because subcutaneous HL-16 and Panc-1 tumors, in contrast to their intramuscular counterparts, develop large central necroses during growth. Moreover, it should be noticed that the histological appearance of intramuscular HL-16 and Panc-1 tumors is similar to that of cervical and pancreatic tumors in humans [25], [30].…”

Section: Discussionmentioning

confidence: 81%

“…In previous studies, we have shown that the development of lymph node metastases is associated with high IFP in the primary tumor in human melanoma, cervical carcinoma, and pancreatic carcinoma xenografts [7], [9], [30], [36], [37]. In those studies, tumor IFP was measured in a single position in the tumor center assuming that IFP was uniformly elevated throughout the central tumor region.…”

Section: Discussionmentioning

confidence: 99%

“…The mice were euthanized immediately after the IFP measurement, and external as well as internal lymph nodes were resected and subjected to detailed histological examination to validate or invalidate the assumed metastatic status. Six pairs of lymph nodes (i.e., the popliteal lymph nodes, inguinal lymph nodes, proper axillary lymph nodes, accessory axillary lymph nodes, medial iliac lymph nodes, and renal lymph nodes) were investigated as described elsewhere [30]. Examples of an enlarged lymph node with metastatic growth, a normal-sized lymph node without metastatic growth, and the histology of a lymph node with metastatic growth are presented in Figure 2.

Figure 2Lymph node metastasis.…”

Section: Methodsmentioning

confidence: 99%

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Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

Hansem¹,

Huang²,

Wegner³

et al. 2019

Translational Oncology

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Preclinical studies have suggested that interstitial fluid pressure (IFP) is uniformly elevated in the central region of tumors, whereas clinical studies have revealed that IFP may vary among different measurement sites in the tumor center. IFP measurements are technically difficult, and it has been claimed that the intratumor heterogeneity in IFP reported for human tumors is due to technical problems. The main purpose of this study was to determine conclusively whether IFP may be heterogeneously elevated in the central tumor region, and if so, to reveal possible mechanisms and possible consequences. Tumors of two xenograft models were included in the study: HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma. IFP was measured with Millar SPC 320 catheters in two positions in each tumor and related to tumor histology or the metastatic status of the host mouse. Some tumors of both models showed significant intratumor heterogeneity in IFP, and this heterogeneity was associated with a compartmentalized histological appearance (i.e., the tissue was divided into compartments separated by thick connective tissue bands) in HL-16 tumors and with a dense collagen-I-rich extracellular matrix in Panc-1 tumors, suggesting that these connective tissue structures prevented efficient interstitial convection. Furthermore, some tumors of both models developed lymph node metastases, and of the two IFP values measured in each tumor, only the higher value was significantly higher in metastatic than in non-metastatic tumors, suggesting that metastatic propensity was determined by the tumor region having the highest IFP.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Figure 2Lymph node metastasis.…”

Section: Methodsmentioning

confidence: 99%

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Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

Hansem¹,

Huang²,

Wegner³

et al. 2019

Translational Oncology

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“…However, an intramuscular site was chosen to avoid tumor movement due to respiration during the DCE-MRI. We have shown previously that intramuscular BxPC-3 and Panc-1 tumors have several microenvironmental features in common with human PDACs, including a histological appearance characterized by a dense collagen-rich extracellular matrix [38] , [45] . Furthermore, the numerical values of fraction of hypoxic tissue, microvascular density, and interstitial fluid pressure of intramuscular BxPC-3 and Panc-1 tumors are similar to those reported for orthotopic and genetically engineered mouse models of PDAC as well as human PDACs [45] .…”

Section: Discussionmentioning

confidence: 99%

DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts

et al. 2018

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The purpose of this study was dual: to investigate (a) whether sunitinib may induce changes in tumor microvasculature and hypoxia in pancreatic ductal adenocarcinoma (PDAC) and (b) whether any changes can be detected by DCE-MRI. Sunitinib-treated and untreated control tumors of two PDAC xenograft models (BxPC-3 and Panc-1) were subjected to DCE-MRI before the imaged tumors were prepared for quantitative analysis of immunohistochemical preparations. Pimonidazole was used as a hypoxia marker, and fraction of hypoxic tissue (HFPim), density of CD31-positive microvessels (MVDCD31), and density of αSMA-positive microvessels (MVDαSMA) were measured. Parametric images of Ktrans and ve were derived from the DCE-MRI data by using the Tofts pharmacokinetic model. BxPC-3 tumors showed increased HFPim, decreased MVDCD31, unchanged MVDαSMA, and increased vessel maturation index (VMI = MVDαSMA/MVDCD31) after sunitinib treatment. The increase in VMI was seen because sunitinib induced selective pruning rather than maturation of αSMA-negative microvessels. Even though the microvessels in sunitinib-treated tumors were less abnormal than those in untreated tumors, this microvessel normalization did not improve the function of the microvascular network or normalize the tumor microenvironment. In Panc-1 tumors, HFPim, MVDCD31, MVDαSMA, and VMI were unchanged after sunitinib treatment. Median Ktrans increased with increasing MVDCD31 and decreased with increasing HFPim, and the correlations were similar for treated and untreated BXPC-3 and Panc-1 tumors. These observations suggest that sunitinib may induce significant changes in the microenvironment of PDACs, and furthermore, that Ktrans may be an adequate measure of tumor vascular density and hypoxia in untreated as well as sunitinib-treated PDACs.

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“…Euthanized mice were examined for lymph node metastases in six pairs of lymph nodes ( i.e. , popliteal lymph nodes, inguinal lymph nodes, proper axillary lymph nodes, accessory axillary lymph nodes, medial iliac lymph nodes, and renal lymph nodes), as described elsewhere [ 46 ]. The presence of metastatic growth in lymph nodes was confirmed by histological examination.…”

Section: Methodsmentioning

confidence: 99%

Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation

et al. 2018

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Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors. Late generation tumors showed higher incidence of lymph node metastases than early generation tumors in three models (ED-15, HL-16, LA-19), and the increased metastatic propensity was associated with increased tumor growth rate, increased microvascular density, and increased expression of angiogenesis-related and cancer stem cell-related genes. Furthermore, late generation tumors showed decreased fraction of pimonidazole-positive tissue (i.e., decreased fraction of hypoxic tissue) in two models (HL-16, LA-19) and decreased fraction of collagen-I-positive tissue (i.e., less extensive extracellular matrix) in two models (ED-15, HL-16). This study showed that serially transplanted PDXs may not necessarily mirror the donor patients’ diseases, and consequently, proper use of serially transplanted PDX models in translational cancer research requires careful molecular monitoring of the models.

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Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts

Cited by 11 publications

References 77 publications

Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts

Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation

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