Modern cancer therapies have significantly increased patient survival rates in both human and veterinary medicine. Since cancer patients live longer they now face new challenges resulting from severe, chronic tumor-induced pain. Unrelieved cancer pain significantly decreases the quality
of life of such patients; thus the goal of pain management is to not only to alleviate pain, but also to maintain the patient's physiological and psychological well-being. The major impediment for developing new treatments for cancer pain has been our limited knowledge of the basic mechanisms
that drive cancer pain and the lack of adequate animal cancer pain models to study the molecular, biochemical and neurobiological pathways that generate and maintain cancer pain. However this situation has recently changed with the recent development of several novel animal models of cancer
pain. This review will focus on describing these animal models, many of them in rodents, and reviewing some of the recent information gained from the use of these models to investigate the basic mechanims that underlie the development and maintenance of cancer pain. Animal models of cancer
pain can be divided into the following five categories: bone cancer pain models, non-bone cancer pain models, cancer invasion pain models, cancer chemotherapeutic-induced peripheral neuropathy models, and spontaneous occurring cancer pain models. These models will be important not only for
enhancing our knowledge of how cancer pain is generated, but more importantly for the development of novel therapeutic regimes to treat cancer pain in both domestic animals and humans.
The frequent occurrence of fatigue and disturbed sleep in cancer survivors and the negative effect of these symptoms on quality of life and clinical outcome underscore the need to identify mechanisms that cause cancer-related fatigue, with a view toward developing more effective treatments
for this problem. Human studies of fatigue and disturbed sleep are limited by high inter-individual genetic and environmental variability, difficulties with behavioral or reporting compliance, and the subjective nature of the problems. Although animal models also must overcome the barrier
of assessing fatigue and sleep disturbance in the absence of obvious objective clinical markers, animal studies are easier to control and standardize than are studies of people. Moreover, animal models are crucial to the identification and understanding of underlying disease mechanisms. This
review describes the need for, the feasibility of, and several possible approaches to measuring fatigue in animal models of cancer and to relating such measures to disturbed sleep, immune function, and other potential mechanisms. Developing and using animal models to better understand fatigue
and disturbed sleep related to cancer and its treatment has an enormous potential to expand the knowledge base and foster hypotheses necessary for the future development and testing of interventions.
CD45R/B220 antigen (B220) is a common mouse panB-cell marker used for paraffin-embedded tissues. However, antiB220 has limited specificity in diagnostic pathology because the B220 antigen is expressed on subsets of cytotoxic T lymphocytes and natural killer cells, on plasmacytic dendritic
cells, and on T lymphocytes of mice with the lymphoproliferative disorder associated with Fas (lymphoproliferative mutant mouse, B6.MRL-Faslpr/J) or Fas ligand (generalized lymphoproliferative disease mutant mouse, C3H/HeJ-Faslgld/J or B6Smn.C3-Faslgld/J).
In addition, mouse B lymphocytes vary in the amount of B220 expressed, and some subsets of mouse B lymphocytes do not express B220 at all. In comparison, Pax5 expression (detected by immunohistochemistry using antiPax5) offers greater specificity and sensitivity because of its earlier expression
during B-cell differentiation, its ability to detect all committed B cells, and its restriction to the B-cell lineage. Here we describe the use of an antibody to human Pax5 in diagnostic pathology with formalin-fixed, paraffin-embedded mouse tissue.
The inbred FVB mouse strain is used extensively in cancer research. Transgenic mice with an FVB/N background in which the expression of green fluorescent protein is under the control of various promoters have been used widely for the last decade. However, little is known about the incidence
and characteristics of spontaneous tumors in these mice. In addition, only a few tumor lines have been established for use in this particular mouse strain. Our aim was to initiate a database of spontaneous tumors in our retired FVB/N breeders, analyze the histopathologic characteristics of
these tumors, and establish novel tumor lines in vivo and in vitro. A total of 234 (40 male, 194 female) breeder mice were observed during their natural lifespans. The incidence of spontaneous tumors was 45.0% in male mice and 52.8% in female mice. All tumors in male mice were lung alveolar–bronchiolar
(AB) neoplasms, except for 1 testis interstitial cell tumor. In female mice, histopathologic examination revealed 48 lung AB tumors, 27 mammary gland tumors, 13 ovarian tumors, and 14 other tumors. Several of these spontaneous tumors have been transplanted into FVB/N mice. One mammary adenocarcinoma
(MCaP0008) and 1 lung AB carcinoma (LAP0297) were successfully transplanted subcutaneously and passaged serially in vivo. Subsequently, we established cell lines from both tumors, which were maintained in monolayer in vitro. Both of the grafted tumors and cell lines are tumorigenic in VEGFP-GFP/FVB
and Tie2P-GFP/FVB mice. Establishment of these novel tumor lines will benefit both in vivo and in vitro studies on the pathophysiology of cancer in this relatively new but widely used mouse strain.
Tumor size or volume is often the primary endpoint in preclinical efficacy studies of anticancer drugs. Efficient and accurate measurement of such tumors is crucial to rapid evaluation of novel drug candidates. Currently available techniques for acquiring high-throughput data on tumor
volume are time-consuming and prone to various inaccuracies and errors. The laser-scanning technology we describe here provides a convenient, high-throughput system for tumor measurement that reduces interoperator variability and bias while providing automated data collection, processing and
analysis.
Mice in a colony used for pancreatic cancer research and maintained in a barrier animal facility presented with vulvar masses. A census and examination of all colony animals was conducted on 17 February 2006; line, gender, and mass location were recorded; a slide caliper was used to
measure the width, length, and height of each mass; and the volume of each mass was calculated. Progeny female mice from crossbreeding of the B6. FVB-Tg(Ipf1-cre)1Tuv and B6;129-Kras2tm4Tyj (KRASG12D/+) strains presented with external vulvar and periauricular papillomas.
The papillomas were present in 41.2% of all female crossbred mice and ranged in size from 8 to 36 mm3. Age of mice and tumor size were not correlated. Compared with the B6. FVB-Tg(Ipf1-cre)1Tuv line, the crossbred female mice were more likely to have a vulvar mass, with an odds
ratio of 29.3, 95% confidence interval (1.5, 563.9) and a positive predictive value of 42.9%. Diagnostic evaluation, including electron microscopy, light microscopy, serology, and bacteriology, did not reveal a viral or other infectious etiology. Therefore, we speculate that interaction between
the genetic background of the mice and the introduced Kras oncogene may be responsible for these papillomas.
Mutational activation of the gene for epidermal growth factor receptor (EGFR) is 1 of the main ways by which this receptor induces non-small cell lung cancers (NSCLC). Variant III EGFR (EGFRvIII) is a potential therapeutic target in NSCLC treatment because of the high
frequency of deletion mutations in this protein. This study used noninvasive magnetic resonance imaging (MRI) to investigate the role of an EGFRvIII mutant in lung tumorigenesis and tumor maintenance as well as its response to the EGFR small molecule inhibitor erlotinib (Tarceva) on
bitransgenic mice. Both spin-echo and gradient-echo sequences with and without cardiac and respiratory gating were performed to image the invasive mouse lung tumor driven by EGFRvIII mutation. Tumor volumes were measured based on 2-dimensional axial MRI; 3-dimensional rendering of the
images were obtained to demonstrate the spatial location and distribution of the tumor in the lung. The MRI results indicated that the tumor driven by the EGFRvIII mutation was generated and maintained in the bitransgenic mice with the use of doxycycline. Tumor monitoring via MRI showed
that Erlotinib can significantly inhibit the growth of tumor in vivo. MRI has the ability to image mouse lung tumor with different sequences focusing on tissue contrasts between tumor and surroundings. The MRI approaches in this work can be applied on other antitumor drug treatment evaluation
in vivo when appropriate sequences are chosen.
Two common procoagulant activities associated with tumors are tissue factor and cancer procoagulant (CP), an activator of coagulation factor X. We have identified a convenient source of CP in transplanted Lobund–Wistar rat PA3 prostate tumors. CP activity was purified from 5 independent
transplanted prostate tumors by column chromatography. The protein activated factor X in the absence of TF and factor VII. An antihuman CP antibody recognized rat CP in an ELISA and inactivated CP activity in a chromogenic assay. Lobund–Wistar prostate tumors may provide a convenient
animal model useful in determining the role of CP in cancer development.
Primary and secondary pleural cancer remains an important clinical problem, with research progress limited by the lack of a suitable moderate- to large-sized (3 to 4 kg) animal model of pleural cancer. Many potential pleura-based imaging and treatment modalities cannot be investigated
sufficiently by using currently available small murine animal models because their pleural space is not comparable to that of humans and therefore does not allow for the use of standard thoracoscopic techniques. Here we describe the development of a reproducible model of pleural malignancy
in moderate-sized immunocompetent rabbits. Under thoracoscopic guidance, 9–15×106 VX2 carcinoma cells were inoculated into the plural space of 3 to 4 kg New Zealand white rabbits that had undergone gentle pleural abrasion. Malignant tumor involvement developed on the
visceral and parietal pleural surfaces in an average of 2 to 4 wk. This novel pleural tumor model induction method likely will facilitate a broad range of investigations of pleural cancer diagnostics and therapeutics.
A 1.5-y-old female Djungarian hamster (Phodopus sungorus) presented with a large subcutaneous mass surrounding the right shoulder. Radiography revealed dislocation of the right humeral articulation and osteolytic lesions of the right scapula. Histologically, the mass was composed
of spindle to stellate cells arranged in fascicles interwoven with delicate collagen fibers, and neoplastic cells infiltrated the bone, skeletal muscle, and subcutaneous tissues. Neoplastic cells stained intensely positive for vimentin and negative for S100 protein, neurofilament, and desmin.
A minority of neoplastic cells (10% to 20%) stained moderately for smooth muscle actin. The mass was diagnosed as a fibrosarcoma. Although fibrosarcomas are relatively common in dogs and cats, this is the first report of fibrosarcoma in a domestic Djungarian hamster.
A 44-mo-old, female, nulliparous New Zealand White Rabbit (Oryctolagus cuniculus presented with bilaterally diffusely enlarged mammary glands with enlarged, discolored teats that exuded brown, mucoid discharge. The complete blood count and serum chemistry panels were within normal
limits, bacteria were not isolated from a culture of the discharge, and the clinical signs did not resolve with antibiotic treatment. Computed tomography and serum prolactin levels supported the diagnosis of mammary gland dysplasia, possibly due to a prolactin-secreting pituitary adenoma.
Histologic evaluation confirmed the presence of a pituitary adenoma, mammary hyperplasia, dysplasia, and cystic mammary adenocarcinoma. Immunohistochemical staining confirmed the presence of abundant prolactin secreting cells in the pituitary adenoma. This is the second report of hyperprolactinemia
with mammary dysplasia in rabbits, and the first report of cystic mammary adenocarcinoma associated with a prolactin-secreting pituitary adenoma in a rabbit.