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. 2017 Jan;54(1):32-43.
doi: 10.1177/0300985816650243. Epub 2016 Jul 11.

Feline Mammary Cancer

B B Hassan  1   2 , S M Elshafae  1   3 , W Supsavhad  1 , J K Simmons  1 , W P Dirksen  1 , S M Sokkar  2 , T J Rosol  1
Affiliations

Feline Mammary Cancer

B B Hassan et al. Vet Pathol. 2017 Jan.

Abstract

Feline mammary carcinoma (FMC) is similar to human breast cancer in the late age of onset, incidence, histopathologic features, biological behavior, and pattern of metastasis. Therefore, FMC has been proposed as a relevant model for aggressive human breast cancer. The goals of this study were to develop a nude mouse model of FMC tumor growth and metastasis and to measure the expression of genes responsible for lymphangiogenesis, angiogenesis, tumor progression, and lymph node metastasis in FMC tissues and cell lines. Two primary FMC tissues were injected subcutaneously, and 6 FMC cell lines were injected into 3 sites (subcutaneous, intratibial, and intracardiac) in nude mice. Tumors and metastases were monitored using bioluminescent imaging and characterized by gross necropsy, radiology, and histopathology. Molecular characterization of invasion and metastasis genes in FMC was conducted using quantitative real-time reverse transcription polymerase chain reaction in 6 primary FMC tissues, 2 subcutaneous FMC xenografts, and 6 FMC cell lines. The histologic appearance of the subcutaneous xenografts resembled the primary tumors. No metastasis was evident following subcutaneous injection of tumor tissues and cell lines, whereas lung, brain, liver, kidney, eye, and bone metastases were confirmed following intratibial and intracardiac injection of FMC cell lines. Finally, 15 genes were differentially expressed in the FMC tissues and cell lines. The highly expressed genes in all samples were PDGFA, PDGFB, PDGFC, FGF2, EGFR, ERBB2, ERBB3, VEGFD, VEGFR3, and MYOF. Three genes ( PDGFD, ANGPT2, and VEGFC) were confirmed to be of stromal origin. This investigation demonstrated the usefulness of nude mouse models of experimental FMC and identified molecular targets of FMC progression and metastasis.

Keywords: angiogenesis; animal model; bone; brain; cat; lung; lymphangiogenesis; mammary cancer; metastasis.

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Conflict of interest statement

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Primary mammary gland carcinoma (patient CM), cat. The neoplasm was a poorly differentiated solid carcinoma with production of mucoid material. Hematoxylin and eosin.
Figure 2.
Figure 2.
Primary mammary gland carcinoma (patient JF), cat. The neoplasm was a well-differentiated, tubulopapillary carcinoma with papillary projections.
Figure 3.
Figure 3.
Mammary gland carcinoma (patient CM), nude mouse subcutaneous xenograft. The xenograft was a tubulopapillary carcinoma with mucoid material similar to the primary cancer in the cat.
Figure 4.
Figure 4.
Mammary gland carcinoma (patient JF), nude mouse subcutaneous xenograft. The xenograft was a tubulopapillary carcinoma similar to the primary cancer in the cat.
Figure 5.
Figure 5.
Mammary gland carcinoma (FMCm cell line), nude mouse subcutaneous xenograft. The xenograft was a poorly differentiated tubulopapillary carcinoma with extensive necrosis and mild fibrosis.
Figure 6.
Figure 6.
Mammary gland carcinoma (FYMp cell line), nude mouse subcutaneous xenograft. The xenograft consisted of 2 populations of cells: squamous cell carcinoma and tubulopapillary carcinoma.
Figure 7.
Figure 7.
Mammary gland carcinoma (FNNm cell line), nude mouse subcutaneous xenograft. The xenograft was a poorly differentiated solid carcinoma with reactive fibrous tissue.
Figure 8.
Figure 8.
Mammary gland carcinoma (FKNp cell line), nude mouse subcutaneous xenograft. The xenograft was a moderately differentiated basosquamous carcinoma.
Figure 9.
Figure 9.
Mammary gland carcinoma (FONp cell line), nude mouse subcutaneous xenograft. The xenograft was a well-differentiated tubulopapillary carcinoma.
Figure 10.
Figure 10.
Mammary gland carcinoma (FONm cell line), nude mouse subcutaneous xenograft. The xenograft was a well-differentiated basosquamous carcinoma.
Figure 11.
Figure 11.
Growth curves of feline mammary cancer (FMC) cell lines as subcutaneous xenografts in nude mice. FMCm, FNNm, FKNp, and FYMp had a high proliferation rate, while FONp and FONm had a low proliferation rate.
Figure 12.
Figure 12.
Tibia, Nude mouse. Radiograph. (a) Tibia without injection used as control. (b) The FYMp Luc cells in the tibia induced abundant new woven bone formation in the metaphysis and diaphysis (“osteosclerotic” metastasis) (arrow).
Figure 13.
Figure 13.
Tibia, Nude mouse. Radiograph. (a) Tibia without injection used as control. (b) The FKNp Luc cells in the tibia marrow space induced mixed osteolytic/osteoblastic bone metastases in the metaphysis and diaphysis (arrow).
Figure 14.
Figure 14.
Tibia, Nude mouse. FYMp Luc cell line. New woven bone formation was induced by the mammary cancer within the medullary cavity of the diaphysis and along the endosteal surfaces. Hematoxylin and eosin.
Figure 15.
Figure 15.
Tibia, Nude mouse. FMCm Luc cell line. New woven bone formation was induced by the mammary cancer (top of image) within the medullary cavity.
Figure 16.
Figure 16.
Lung, Nude mouse. FMCm Luc lung metastasis. The lung metastasis had an epithelial phenotype.
Figure 17.
Figure 17.
Brain, Nude mouse. FMCm Luc brain metastasis.
Figures 18–29.
Figures 18–29.
The relative mRNA expression of platelet-derived growth factor A (PDGFA), platelet-derived growth factor B (PDGFB), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-3 (VEGFR-3), platelet-derived growth factor C (PDGFC), epidermal growth factor receptors (ERBB3 and ERBB2), myoferlin (MYOF), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor D (VEGFD), angiopoietin 1 (ANGPT1) and parathyroid hormone-related protein (PTHrP), in feline primary mammary cancers (n = 6), nude mouse subcutaneous xenografts (n = 2 at 2 different passages), and mammary cancer cell lines (n = 6). *P < .05, **P < .001. Significant differences were identified for PDGFB, EGFR, VEGFR-3, and MYOF but not for PDGFA, PDGFC, ERBB3, ERBB2, FGF2, VEGFD, ANGPT1, and PTHrP. The mean is presented by the horizontal bars. Figure 18. PDGFA. Figure 19. PDGFB. Figure 20. EGFR. Figure 21. VEGFR-3. Figure 22. PDGFC. Figure 23. ERBB3. Figure 24. ERBB2. Figure 25. MYOF. Figure 26. FGF2. Figure 27. VEGFD. Figure 28. ANGPT1. Figure 29. PTHrP.
Figures 30–32.
Figures 30–32.
Relative mRNA expression of platelet-derived growth factor D (PDGFD), angiopoietin 2 (ANGPT2), and vascular endothelial growth factor C (VEGFC) mRNA based on qRT-PCR using cat-specific and mouse-specific primers. Upper panels: the feline mRNAs were expressed in feline primary mammary carcinomas but not in subcutaneous xenografts or cell lines. Lower panels: in contrast, murine PDGFD, ANGPT2, and VEGFC mRNAs were expressed in the subcutaneous xenografts, which suggests that these genes were expressed only in the tumor stroma and not the epithelial cells.
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