PurposeIt has been implied that the collagen binding integrin α11β1 plays a role in carcinogenesis. As still relatively little is known about how the stromal integrin α11β1 affects different aspects of tumor development, we wanted to examine the direct effects on primary tumor growth, fibrosis, tumor interstitial fluid pressure (PIF) and metastasis in murine 4T1 mammary and RM11 prostate tumors, using an in vivo SCID integrin α11-deficient mouse model.MethodsTumor growth was measured using a caliper, PIF by the wick-in-needle technique, activated fibroblasts by α-SMA immunofluorescence staining and fibrosis by transmission electron microscopy and picrosirius-red staining. Metastases were evaluated using hematoxylin and eosin stained sections.ResultsRM11 tumor growth was significantly reduced in the SCID integrin α11-deficient (α11-KO) compared to in SCID integrin α11 wild type (WT) mice, whereas there was no similar effect in the 4T1 tumor model. The 4T1 model demonstrated an alteration in collagen fibril diameter in the integrin α11-KO mice compared to WT, which was not found in the RM11 model. There were no significant differences in the amount of activated fibroblasts, total collagen content, collagen organization or PIF in the tumors in integrin α11-deficient mice compared to WT mice. There was also no difference in lung metastases between the two groups.ConclusionDeficiency of stromal integrin α11β1 showed different effects on tumor growth and collagen fibril diameter depending on tumor type, but no effect on tumor PIF or development of lung metastasis.
The main objective of this study was to identify single proteins or protein networks that might be used as diagnostic biomarkers or for therapeutic purposes by evaluating the protein expression profiling of plasma and lungs at different stages of metastatic development in a human triple negative MDA-MB-231 breast cancer xenograft model. MDA-MB-231 tumour cells were injected into the mammary fat pads on one side of the groin area. The mice were sacrificed day 19 (pre-metastases) and day 54 (metastases). Non-injected mice served as controls. Plasma was collected and lungs harvested for both immunohistochemistry and protein analysis. The most striking observation in plasma was the initial reduction in haptoglobin level at the pre-metastatic stage, to a following significant increase in haptoglobin level at the metastatic stage, with a more than 4000-fold increase from the pre-metastatic to the metastatic phase. A corresponding increase in haptoglobin level was also found in lung tissue after metastasis. Fibrinogen beta chain also had a similar change in expression level in plasma as haptoglobin, however not as prominent. There were also changes in plasma thrombospondin-4 and transferrin receptor protein 1 levels, from an increase at the pre-metastatic stage, to a significant fall when metastases were established. This suggests that especially changes in haptoglobin, but also fibrinogen beta chain, thrombospondin-4 and transferrin receptor protein 1 is indicative of metastasis, at least in this breast cancer model, and should be further evaluated as general breast cancer biomarkers.
Imaging of clinically relevant preclinical animal models is critical to the development of personalized therapeutic strategies for endometrial carcinoma. Although orthotopic patient-derived xenografts (PDXs) reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by the lack of appropriate imaging modalities. Here, we describe molecular imaging of a near-infrared fluorescently labeled monoclonal antibody targeting epithelial cell adhesion molecule (EpCAM) as an in vivo imaging modality for visualization of orthotopic endometrial carcinoma PDX. Application of this near-infrared probe (EpCAM-AF680) enabled both spatio-temporal visualization of development and longitudinal therapy monitoring of orthotopic PDX. Notably, EpCAM-AF680 facilitated imaging of multiple PDX models representing different subtypes of the disease. Thus, the combined implementation of EpCAM-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform for identification and validation of new targeted therapies and corresponding response predicting markers for endometrial carcinoma.
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