High <scp>COX</scp>‐2 expression is associated with increased angiogenesis, proliferation and tumoural inflammatory infiltrate in canine malignant mammary tumours: a multivariate survival study

Carvalho, Maria Isabel; Pires, Isabel; Prada, Justina; Raposo, Teresa P; Gregório, Hugo; Lobo, Lurdes; Queiroga, Felisbina L.

doi:10.1111/vco.12206

Cited by 43 publications

(52 citation statements)

References 50 publications

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“…In the present study, firocoxib, a selective cyclo-oxygenase-2 (COX2) inhibitor, was chosen. Carvalho et al demonstrated an association between COX2 expression and aggressive biological behavior, including shorter survival, metastasis, and angiogenesis, emphasizing the usefulness of selective COX2 inhibitors in the treatment for canine mammary tumors (54).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms

Campos

Lavalle

Monteiro³

et al. 2018

In Vivo

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Background/Aim: The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC). Materials and Methods: Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated. Results: No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001). Conclusion: The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages. Many mammalian species present mammary gland neoplasms similar to breast cancer in women, and the high incidence of spontaneous disease in domestic dogs and cats characterize them as pertinent comparative models (1). Human and canine breast cancer incidence present similar proportional distribution by age and sex (2), and resemblance in type, molecular transformative abnormalities, and behavior. This enables comparative studies involving carcinogenesis and the efficacy of novel therapies in mammary neoplasms in pets (1). Mammary gland neoplasms are the most common neoplasms that affect female dogs (3). Although the optimal extent remains unclear (4), surgery remains the most effective treatment for the disease. Adjuvant therapies may be required for high-risk, undifferentiated and advanced neoplasms (5, 6). Single-agent treatments have been considered less efficacious than combination therapies (7), and in solid tumors, angiogenesis has clearly been associated with metastasis and disease progression (8), and the combination of antiangiogenic strategies with conventional chemotherapy protocols will likely benefit the treatment of malignant tumors (9). In the late 1950s, thalidomide was marketed worldwide as a sedative and a hypnotic, and as an anti-emetic drug in early pregnancy (10). Thalidomide was associated with congenital deformities and peripheral neuropathy, and the drug was 1659 This article is freely accessible online.

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Section: Discussionmentioning

confidence: 99%

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms

Campos

Lavalle

Monteiro³

et al. 2018

In Vivo

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“…In canine mammary tumors there are only a limited number of studies focusing on the cross talk between COX-2, cancer cells, and immune cells [19, 73] and this topic is incompletely understood. Our team demonstrated a significant association of high COX-2 immunoexpression with CD3 + T-lymphocytes [19] and MAC387 macrophages [73].…”

Section: Inflammatory Cells and Cancer Cell Biomarkersmentioning

confidence: 99%

“…Our team demonstrated a significant association of high COX-2 immunoexpression with CD3 + T-lymphocytes [19] and MAC387 macrophages [73]. Tumors with concurrent high COX-2/CD3 and high COX-2/MAC were statistically associated with variables of tumor aggressiveness (high histological grade of malignancy, presence of neoplastic intravascular emboli, and presence of lymph node metastasis) and shorter overall survival of animals [73]. These findings suggest that, similarly to human breast cancer, T-lymphocytes, macrophages, and COX-2 share functions in canine mammary carcinogenesis.…”

Section: Inflammatory Cells and Cancer Cell Biomarkersmentioning

confidence: 99%

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

Carvalho

Silva-Carvalho

Pires

et al. 2016

BioMed Research International

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Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

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“…COX-2 expression has been associated with proliferation and angiogenesis in canine mammary tumours and mast cell tumours [16], but associations with these pathways have not been well established in canine melanocytic tumours.…”

Section: Introductionmentioning

confidence: 99%

Investigating associations of cyclooxygenase-2 expression with angiogenesis, proliferation, macrophage and T-lymphocyte infiltration in canine melanocytic tumours

et al. 2016

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Cyclooxygenase-2 (COX-2) is known to be involved in tumour progression and has been suggested as a therapeutic target in many human and animal malignancies. A number of different pathways subjacent to cancer hallmarks are considered to be involved in COX-2-mediated tumour progression, although these are still largely undefined. Our aim is to investigate associations between COX-2 expression and angiogenesis, proliferation and the inflammatory microenvironment in canine melanocytic tumours. Understanding the involvement of COX-2 with cancer hallmarks might enable us to adapt therapeutic strategies for canine melanomas, an aggressive and often lethal malignancy with value in comparative oncology. Immunohistochemical staining of COX-2, Ki-67 (proliferation index), vascular endothelial growth factor (VEGF), factor VIII (microvessel density), CD3 (lymphocytes) and MAC387 (macrophages) was performed in 51 melanocytic tumours (31 malignant melanomas, 20 melanocytomas). Statistical associations between COX-2 and the other parameters detected were analysed. In melanocytic tumours (n=51), both COX-2 labelling extension and intensity showed a statistically significant association with angiogenesis by factor VIII, VEGF, Ki-67, CD3+ T lymphocytes and MAC387. Within malignant melanomas, COX-2 expression has shown significant associations with microvessel density (factor VIII), lymphocyte and macrophage infiltration and, considering all melanocytic tumours, COX-2 was also associated with VEGF intensity and Ki-67 cell proliferation. Our results point to a role for COX-2 in angiogenesis and in the establishment of an inflammatory microenvironment, favourable to melanoma tumour progression. Further mechanistic studies are warranted to dissect molecular pathways in which COX-2 is involved. Present evidence suggests that COX-2 inhibitors might be useful as an adjuvant treatment to hinder canine melanoma progression.

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High COX‐2 expression is associated with increased angiogenesis, proliferation and tumoural inflammatory infiltrate in canine malignant mammary tumours: a multivariate survival study

Cited by 43 publications

References 50 publications

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

Investigating associations of cyclooxygenase-2 expression with angiogenesis, proliferation, macrophage and T-lymphocyte infiltration in canine melanocytic tumours

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