Background Despite decades of research, the early phases of metastatic development are still not fully understood. Canine osteosarcoma (OS) is a highly aggressive cancer, with a high metastatic rate (> 90%), despite a low overt metastatic prevalence at initial diagnosis (< 15%). Canine OS is generally regarded as a good clinically relevant model for human OS. The aim of this hypothesis-generating study was to evaluate a method to detect pulmonary micrometastases and study their prevalence in dogs with OS without macroscopic metastases. We prospectively enrolled dogs with OS that received no cancer-specific treatment (n = 12) and control dogs without cancer (n = 2). Dogs were necropsied and sampled immediately after euthanasia. The OS dogs were classified as having macroscopic metastases (n = 2) or not (n = 10). We immunohistochemically stained one tissue sample from each of the seven lung lobes from each dog with a monoclonal antibody (TP-3) to identify micrometastases (defined as clusters of 5–50 tumour cells), microscopic metastases (> 50 tumour cells) and TP-3 positive single cells (< 5 tumour cells). Results We showed that pulmonary micrometastases easily overseen on routine histology could be detected with TP-3. Pulmonary micrometastases and microscopic metastases were present in two dogs with OS without macroscopic metastases (20%). Micrometastases were visualised in three (43%) and four (57%) of seven samples from these two dogs, with a mean of 0.6 and 1.7 micrometastases per sample. Microscopic metastases were present in one (14%) and four (57%) of seven samples from the same two dogs, with a mean of 0.14 and 1.0 microscopic metastases per sample. There were four (57%) and two (29%) samples with neither microscopic metastases nor micrometastases for each of these two dogs. The prevalence of pulmonary micrometastases (20%) was significantly lower than expected (> 90%) based on commonly expected metastatic rates after amputation (P < 0.0001). There was no statistically significant difference in the number of TP-3 positive single cells in between groups (P = 0.85). Conclusions Pulmonary micrometastases could be detected with TP-3 immunohistochemistry in a subset of dogs with OS before macroscopic metastases had developed. We propose that dogs with spontaneous OS represent clinically relevant models to study early micrometastatic disease.
Tumor-associated macrophages (TAMs) are heterogeneous and abundantly present in the tumor stroma. They derive from tissue-resident macrophages and recruited monocytes and play a central role in several aspects of cancer. In murine models, TAMs promote invasion, intravasation, circulatory survival and extravasation of tumor cells. TAMs also promote tumor progression and angiogenesis, remodel the tumor microenvironment, and modulate the adaptive immune system. Evidence suggests TAMs are vital for establishing the premetastatic niche. Historically, family-owned dogs have proven to be reliable cancer models. In contrast to laboratory animals, dogs develop cancer naturally and commonly, co-inhabit our environment, are genetically outbred and immunologically experienced. We hypothesized that canine tumor conditioned monocyte-derived macrophages (TCMs) share many characteristics with M2 macrophages and have a tumor-promoting phenotype as in humans. We collected blood from healthy dogs, isolated peripheral blood monocytes and differentiated them in vitro using tumor conditioned media from three canine cancer lines and M-CSF. Three TCM populations were generated and compared with M1 and M2 macrophages. We assessed the macrophages using multicolor flow cytometry and RNA-sequencing. All TCM showed an increased expression of two M2 markers (CD209a and FcɛRI), while 2/3 TCM populations had increased expression of two additional M2 markers (CD206 and CD11d). Transcriptomic analysis is ongoing. Results so far support the hypothesis that canine TCMs share many similarities with human TCMs, further warranting the use of dogs as cancer immunology models. Supported by grant from Agria Animal Insurances (N-2020-0061) and The Research fund for cancer in dogs (Oslo, Norway)
Norway, due to a 1-week history of anorexia, progressive lethargy and occasional vomiting. The dog was fully vaccinated and had no history of travel, previous disease or medication. Upon presentation, the dog was lethargic with pale and tacky mucous membranes, a heart rate of 120 beats per minute and thready femoral pulses.On palpation, the abdomen was distended but not painful. Physical examination was otherwise unremarkable.A complete blood count showed a moderate normocytic normochromic regenerative anaemia, mild monocytosis and mild thrombocytopenia, which was confirmed on blood smear examination (Table 1). Serum biochemistry showed a mild hypoproteinaemia, mild hypoglobulinaemia, mild hypocholesterolaemia and moderately increased C-reactive protein (Table 1). Activated partial thromboplastin time and prothrombin time were not prolonged (aPTT 67s, reference 72-102 s, PT 14s, reference 11-17 s, IDEXX Coag Dx Analyzer). Urinalysis revealed a moderate bilirubinuria (100 μmol/L, IDEXX UA Strip). On abdominal ultrasound performed by a boardcertified radiologist, the spleen had moderately rounded margins with mild diffuse reduced echogenicity and multifocal, ill-defined, slightly hypoechoic lesions scattered throughout the entire parenchyma. The splenic lymph nodes were slightly enlarged. Thoracic radiographs were unremarkable.Cytology smears from the spleen and liver were evaluated by a board-certified clinical pathologist. Splenic cytology was highly cellular and dominated by erythroid precursor cells, but also low numbers of myeloid precursor cells and high numbers of megakaryocytes.
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