Abstract
Comparative oncology is a field of study that has been recently adopted for studying cancer and developing cancer therapies. Companion animals such as dogs can be used to evaluate novel biomarkers or anticancer targets before clinical translation. Thus, the value of canine models is increasing, and numerous studies have been conducted to analyze similarities and differences between many types of spontaneously occurring cancers in canines and humans. A growing number of canine cancer models as well as research-grade reagents for these models are becoming available, leading to substantial growth in comparative oncology research spanning from basic science to clinical trials. In this review, we summarize comparative oncology studies that have been conducted on the molecular landscape of various canine cancers and highlight the importance of the integration of comparative biology into cancer research.
Similar content being viewed by others
An overview of cancer research
Cancer is a disease that affects populations worldwide, with one in three people developing cancer in their lifetime1. Cancer is usually characterized by the uncontrolled division of cells, which become malignant and form metastases that affect other healthy organs in the body1. Cancer can develop almost anywhere in the human body, which is made up of trillions of cells2. Normally, human cells grow and multiply to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place2. Sometimes, however, when this orderly process is disrupted, abnormal or damaged cells grow and multiply when they should not. This can lead to the formation of tumors2. As tumorigenesis progresses, complex changes occur inside and outside the cell1. In particular, genetic mutations and epigenetic changes occur in cancer cells due to various factors1,2. Epigenetic changes, in particular, chromatin structure alterations due to DNA methylation and/or histone modification, occur and eventually lead to the dysregulation of oncogenes or tumor suppressor genes1,2. Tumorigenesis is also associated with cancer-related immune system problems3, including dysregulation of metabolism4. In addition, a cancer-specific tumor microenvironment forms extracellularly, leading to cancer spread and/or metastasis and enhancement of aggressive cell behaviors5. Various studies have focused on the genetic, metabolic, and immunological basis of cancer (Fig. 1). In addition to these studies, this review introduces comparative oncology research as a new perspective on cancer.
Cancer can be interpreted as a genetic disease, a metabolic disease, and an immune disease.
Cancer as a genetic disease
Cancer has long been regarded as a genetic disease, and various studies have been conducted on its genetic basis2,6. These studies provide strong evidence for the genetic basis of cancer, i.e., the notion that cancer is a disease that results from the accumulation of genetic alterations, mutations, and epigenetic changes in key genes that regulate cell growth, division, and replication2,6. Depending on the effects of genetic alterations of key genes in cancer development, these genes are divided into oncogenes and tumor suppressors2. Genetic models of cancer development have provided important insights into the genetic processes that determine cancer initiation, progression, metastasis, the response to therapy, and the development of drug resistance2,6.
A representative example is that mutations in TP53 are found in ~38–50% of many cancers, including ovarian cancer, esophageal cancer, colon cancer, head and neck cancer, laryngeal cancer, and lung cancer cases, although they are not observed in all cancers7. The identification of targets based on the genetic characteristics of tumors, the development of tumor-specific drugs and the identification of patients who may benefit from such treatments are important challenges in overcoming cancer.
Cancer as a metabolic disease
Recently, cancer has received much attention as a metabolic disease rather than a genetic disease. Several key metabolites identified in cancer (e.g., acetate, lactate, serine, sarcosine, asparagine, or choline) are found in almost all cancers, regardless of genetic modification8. The discovery of these different metabolic events may provide important insights into cancer and be useful for cancer diagnosis. For example, recent studies of metabolites in colon polyps and early-stage pancreatic cancer showed that metabolites can serve as biomarkers9,10.
Further evidence that cancer is a metabolic disorder is being confirmed by nucleocytoplasmic transfer research11. These studies aim to identify the origin of cancer by replacing damaged mitochondria or nuclei of cancer cells with normal mitochondria and nuclei12. If the cancer starts in a cell with a damaged nucleus, replacing it with a healthy nucleus should inhibit tumor growth. However, if the cancer originates from metabolic dysregulation due to mitochondrial dysfunction, restoring mitochondrial function may prevent cancer12. In this context, studies interpreting cancer as a metabolic disease are being conducted to overcome cancer, and these studies include targets such as glucose, glutamine, and fatty acid metabolism11,12.
Cancer as an immunological disease
Much research has been conducted to interpret and treat cancer, both solid and hematological, as an immunological disease, and numerous approaches are being pursued worldwide. In this regard, it is very important to understand how the immune system influences the development and progression of cancer3. According to a recent study, immune escape due to tumor induction and tumor-induced alterations in the stromal tissue and immune system around the cancer mass is very important. Suppression of antigen exposure and presentation by malignant cancer cells, abnormal expression of certain chemokines and cytokines, induction of apoptosis in immune cells, and loss of immune cell function are associated with tumor evasion of recognition and elimination by the immune system13. Importantly, both adaptive and innate responses can be disrupted in the tumor microenvironment. As a result, many therapies modulating the immune system have been developed; these include immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies, which exploit a person’s immune system or immune cells to kill cancers.
Recently, there have been advances in methods of diagnosing and treating cancer in the new research area of molecular biology. Genetic, epigenetic, and omics approaches have provided a wealth of information to study the development and progression of cancer and to interpret different aspects of cancer, such as genetic, metabolic, and immunological aspects. Nevertheless, the mechanisms of tumorigenesis need to be further explored and investigated to find successful therapies for all types of cancer.
Limitations in current cancer research
There are many proposed causes and mechanisms to explain the formation and progression of various cancers. Although there have been extensive studies on the pathogenesis of human cancer, there are numerous limitations associated with traditional preclinical research methods that tend to focus on cancer cells grown in 2-dimensional (2D) or 3D cultures or murine xenograft models to assess the efficacy of cancer agents; these limitations have contributed to the high drug attrition rates. In addition, there are some limitations to overcoming cancer14 (Fig. 2): (1) Limitations related to targeting cancer stem cells (CSCs), (2) anticancer drug immunity due to drug resistance of cancer stem cells, (3) lack of cancer epigenetic profiles and specificity of existing epi-drugs, (4) treatment difficulties due to problems related to cancer diagnosis, (5) lack of effective biomarkers for cancer diagnosis and prognosis, (6) limitations of conventional chemotherapeutic agents, and (7) problems in treating cancer metastasis14.
There are still limitations to overcoming cancer for the following reasons: limitations regarding targeting of cancer stem cells (CSCs), anticancer drug immunity due to drug resistance of cancer stem cells, lack of cancer epigenetic profiles and specificity of existing epi-drugs, treatment difficulties due to problems related to cancer diagnosis, lack of effective biomarkers for cancer diagnosis and prognosis, limitations of conventional chemotherapeutic agents, and problems in treating cancer metastasis.
Therefore, the identification of novel biomarkers for human cancer and the discovery of new therapeutic candidates are essential to overcoming the major obstacles to improving existing therapies for the treatment and prevention of cancer. Ultimately, we highlight the importance of comparative research on cancer that occurs naturally in companion animals that share a living environment with humans as a new approach to studying cancer prevention and treatment.
Comparative oncology: new insights into a human cancer
Comparative oncology is the study of cancers in companion animals for the determination of their translational relevance to human cancers15. Numerous types of cancers naturally occur in many types of companion animals, such as dogs, cats, rabbits, and horses16,17. A significant number of canine cancers are diagnosed every year, and dogs are very popular companion animals. Moreover, the ever-increasing accessibility of canine-specific reagents, resources, and scientific literature is opening up avenues for comparative oncology research between canines and humans (Fig. 3).
Companion animals and humans share very similar living environments, exposing both species to similar toxic substances, viruses, and/or pollution. From these external stimuli, companion animals and humans develop cancer from genetic/epigenetic alterations, metabolic changes, and/or immune-related changes.
Much of the research on human cancers is based on mouse models due to their advantages, such as their small size and cost-efficiency18. Nevertheless, mouse models of cancer have limitations in mimicking human cancers because tumors arise spontaneously in humans, whereas tumor formation must be induced in mouse models. As a result, mouse models of human cancers usually lack any gene networks and interactions that account for tumorigenesis in humans.
Canines are excellent models for comparative oncology since they spontaneously develop the same types of cancers as humans. The histological types of these cancers are similar between dogs and humans. There is strong evidence that canines and humans share similar genes and pathways involved in tumorigenesis (Table 1). For example, it has been reported that BRCA1 and BRCA2 SNP markers are notably associated with mammary cancers in English Springer Spaniels and in breast cancers in humans15.
In fact, 1 million out of 77 million dogs in the United States develop cancer each year; 50% of canine cancers develop in animals 10 or more years old, and a quarter of all dogs will develop cancer during their lifetime19. In this context, the United States launched the Canine Comparative Oncology Genomics Consortium (CCOGC) research project at the National Cancer Center (NCI) in 2004 to create a biorepository of canine cancer tissues and blood samples to decode their genes to conduct cancer research. Nevertheless, the last decade’s work on canine cancers focused on tumor biology, pathology, and genetics, and epigenetic pathways has not been thoroughly analyzed. Consequently, in this review, we aim to examine any epigenetic signatures that are shared by cancers in dogs and humans, which is of special interest. It is known that the noncoding regulatory regions of canine genomes are more similar to human genomes than mouse genomes are20. Our recent studies involving genomic and epigenomic comparisons across tissues of different species also revealed that chromatin map overlaps more between canines and humans (~40–50%) than between mice and humans (~10–20%). Furthermore, we also found that super enhancers were more highly conserved between canines and humans (~90% at ~50% minimum mismatch ratio) than between humans and mice (~30% at ~50% minimum mismatch ratio)21. Thus, the epigenetic changes affected by the environment might be more similar between canines and humans than between mice and humans. Therefore, we focused on comparing genetic and epigenetic aspects in canine and human cancers.
Canine cancer models for comparative medicine
Breast cancer
Human breast cancer became the most common cancer globally in 2021, accounting for 12% of new cancer cases worldwide according to the World Health Organization. Breast cancer is a disease in which malignant tumor cells form in the tissues of the breast, and it can be found in both men and women worldwide22. More specifically, breast cancer cells tend to form in the terminal ductal lobular unit, which is made up of the lobe and the ducts23. At the molecular level, breast cancer can be categorized into five molecular subtypes depending on the hormone receptors the cells express: Luminal A (ER/PR+, HER2−), luminal B (ER/PR+, HER2+), HER2-enriched (ER/PR−, HER2+), triple-negative (ER/PR−, HER2−), and normal-like (ER/PR+, HER2−, KI67−)24. These classifications are based on the presence or absence of estrogen, progesterone, and HER2 receptors. Breast cancer subtyping is important for treatment decision making25.
Canine mammary tumors and human mammary tumors are similar in various aspects, such as hormonal dependence, metastasis pattern, relative age of onset, and role of environmental factors at the onset of the disease26. Approximately 60% of human cancers and 45% of canine breast cancers are estrogen receptor-positive27, and recent evidence suggests that many pathological and molecular similarities also exist between canine and human mammary tumors28. More recently, mammary tumor phenotypes found in humans, such as luminal A, luminal B and triple-negative (basal-like), have been identified in canines29. Comparative gene expression profiling and whole-exome sequencing studies between canine and human breast cancers revealed similarities such as cell cycle activation, WNT–β-Catenin signaling, PI3K–AKT and ERK signaling and mutations in ESR1 and BRCA230. Moreover, loss of tumor suppressors such as CDKN2A, PTEN, CDH1 (which encodes E-cadherin) and TP53 was also observed in canine mammary tumors30 (Fig. 4). We previously performed high-throughput whole-exome sequencing using a total of 20 pairs of canine mammary gland tumors and adjacent normal tissues for genomic DNA isolation as a model for mammary gland tumors in dogs31. We found seven significantly mutated genes (SMGs) whose mutation rates were significantly higher than the background mutation rate in canine mammary tumors (CMTs) and reported that the PIK3CA gene was the most frequently mutated in CMT (45%). All somatic mutations identified in the PIK3CA gene resulted in corresponding amino acid sequence changes at six different loci, two variants (c.1637A > C and c.3140A > G) of which were identified as hotspots in CMT31. Analysis of an additional 62 CMT specimens reported that ~18 (~29%) harbored the PIK3CA (A3140G) mutation. The hotspot mutations in canine mammary gland tumors were an exact match for previously reported hotspot PIK3CA mutations in human breast cancer with a prevalence of ~30%31. This is very noteworthy from a comparative medicine point of view. Moreover, canine PIK3CA has a remarkable 99.8% DNA sequence identity to human PIK3CA and 99% amino acid identity to the encoded protein31. The location of the hotspot somatic mutation [nt 3140A > G (aa 1047His > Arg)] was exactly the same in both species31. In this respect, the mutational information of naturally occurring canine cancer provides valuable perspectives for translational comparative medicine studies for human cancer.
Canine mammary cancers (left panel) are typically categorized by histological subtype. On the other hand, human breast cancers (right panel) are usually categorized based on the presence or absence of hormone receptors. Numerous molecular and signaling pathway alterations (middle panel) are observed in both canine and human species.
HER2 status has been investigated in numerous studies in canine mammary tumors to emphasize the similarity between canine and human cancers32. Multiple methods have been used to identify and classify HER2 expression in canine mammary tumor tissues; however, there is still a lack of validated methods for canine-specific HER2 detection, scoring, and clinical relevance33. More specifically, the association between HER2 status and tumor stage, grade, or clinical outcome still needs to be analyzed in canine mammary tumor models. Therefore, the status and role of HER2 expression in canine mammary tumors still needs to be further scrutinized to determine if it is a diagnostic, therapeutic and/or prognostic marker.
In an epigenetic study, our group first comprehensively profiled CMT methylation and inspected its correlation with the human breast cancer methylome34. We also suggested that changes in intron methylation play an important role in CMT by altering TF binding affinity34. The importance of intron methylation was further confirmed in human breast cancer data by the anti-correlation of LRIG1 gene expression with intronic hypermethylated PAX5 and hypomethylated PAX6 motifs34. Genome-wide methylation profiling was also performed in CMT and adjacent normal tissues coupled with matching PBMCs obtained from canines35. Methylation profiling in CMT identified miRNA candidates associated with human breast cancer. This study successfully revealed CMT-enriched differentially methylated regions (DMRs) in both tissues and PBMCs, and the putative roles of DMRs were characterized by GO and pathway analysis of associated genes35. As expected, many apoptosis-related genes, including ARHGEF2, TNFRSF12A, and SFRP2, were hypermethylated in CMT, and some oncogenes in human cancers, such as HRAS, FAM83H, and RET, were found to be hypomethylated35. Ultimately, these results suggest that molecular similarities between CMT and human breast cancer exist not only at the genomic and transcriptomic levels but also at the epigenomic level. As another example of epigenetic regulation, we assessed the diagnostic value of repeated, abundant, but strongly cancer-associated LINE-1 methylation in cfDNA isolated from small amounts of plasma from CMT and HBC subjects in previous studies36. Canine LINE-1 hypomethylation clearly differentiated subjects with CMT from healthy controls, and the same approach was applied to human breast cancer36. Altogether, these data suggest that the comparative approach using a canine model might aid in the rapid development of a new diagnostic biomarker and that the methylation of LINE-1 in cfDNA may be a good t a diagnostic marker for both human BC and CMT36.
Additionally, we sequenced total RNA from ten pairs of CMT tissues and matching adjacent normal tissues to identify CMT-associated transcriptomic signatures37. By comprehensive transcriptome analysis, 351 differentially expressed genes (DEGs) were identified in CMT37. Comparative analysis based on the DEGs revealed correlations between the three histological subtypes of CMT (ductal, simple, and complex) and four molecular subtypes of human BC (HER2+, ER+, ER&HER2+, and TNBC)37. Eight DEGs shared by all three subtypes of CMT had been previously reported as cancer-associated genes in human studies37. In addition, we previously published comparative medical studies with proteomics analysis in human breast cancer and CMT38. In the study, comparative analysis of canine and human cases revealed that the plasma protein LCAT was found a biomarker for advanced breast cancer as well as mammary tumors undergoing metastasis38.
Although limited, these reports indicate that canine mammary tumors share numerous downstream oncogenic alterations with human breast cancers and suggest potential for comparative research and drug development.
Prostate cancer
Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide39. Prostate cancer is also found in canines, and it is more serious than in humans since prostate cancer is usually diagnosed at advanced stages in dogs, resulting in short overall survival and poor quality of life40,41. The incidence of prostate cancer in both species constitutes a model for therapies for advanced prostate cancers in humans42. Prostate cancer can be treated with local and systemic therapies and with nonsteroidal anti-inflammatory drugs (NSAIDs) in both canines and humans43,44.
Nevertheless, a large difference exists in that human prostate cancer is dependent on androgens, whereas canine prostate cancer is androgen-independent45. In the male reproductive system, androgens play a key role in the testes and adrenal glands, producing steroid hormones such as testosterone and dihydrotestosterone46. These hormones physically bind to androgen receptors, ultimately regulating gene expression that is involved in protein secretion, gene fusion, cell growth stimulation, growth factor production, and cell cycle regulation47. As a result, androgen receptors are directly responsible for the onset and progression of prostate cancers with numerous underlying mechanisms, such as receptor amplification or mutation, androgen biosynthesis changes, and/or androgen receptor binding cofactor changes, resulting in transcriptional activity modification48,49. However, there are now reports showing that many human prostate cancer patients develop the disease through pathways unrelated to androgen receptors50,51. In this line, canine prostate cancer, which is unaffected by androgen receptor aberrations, can serve as a good model. Not only does it mirror androgen-independent human prostate cancer, but it is also clinically similar to hormone-resistant human prostate cancer.
Consequently, comparative medical techniques can be utilized to characterize any DNA copy number aberrations, changes in signaling pathways, and expression of cancer-related genes, ultimately leading to alterations in molecular interaction networks. Moreover, canine-human interspecies cross-validation analysis revealed 79 genes that were simultaneously altered, further proving the molecular similarities behind human and canine prostate cancer40. These genes include ADRA1A, CCL17, CDH1, CFDP1, CHST4, CLU, CNGB1, CX3CL1, CYBA, EIF4A1, GALNS, GP1BA, GUCY2D, HSF4, MC1R, MX1, MYH1, NIP7, PLA2G15, SLC7A5, and TP5340. As an example, the tumor suppressor gene phosphatase and tensin homolog (PTEN) and oncogene signal transducer and activator of transcription 3 (STAT3) are known to be dysregulated in human prostate cancer and are linked to increased malignancy and a poor prognosis52. According to research, canine prostate carcinogenesis is also involved in the overexpression of STAT3 and downregulation of PTEN, and both indicators may be associated with the histological subtypes of prostate cancer and the degree of differentiation of neoplastic cells52. Moreover, VEGFR-2 appears to be an independent prognostic factor in animals with prostate cancers53. VEGF-A and VEGFR-2 are highly conserved between humans and canines53. In addition to the similarities, differences between canine and human prostate cancer exist. Highly prevalent alterations in human prostate cancer, such as gains of the MYC oncogene and deletions of the tumor suppressors NKX3-1, PTEN, RB1, and CDKN1B, were either absent or present in only very limited cases40.
Lung cancer
Lung cancer is by far the leading cause of human cancer death, accounting for one-fourth of all cancer deaths54. Lung cancer can be classified largely into two histopathological subtypes: non-small-cell lung cancer (NSCLC; accounts for 85%) and small-cell lung cancer (SCLC; 15%). NSCLC can be further categorized into adenocarcinoma, squamous cell carcinoma, and bronchoalveolar and large cell carcinoma54. SCLC occurs in neuroendocrine cells of the bronchus55.
Unlike humans, lung cancer is rarely observed in dogs. The incidence is 1% in canines56. Surgery is the main form of therapy for both canines and humans; however, there is a heightened possibility of recurrence and metastasis in canines57. As a result, targeted systemic therapy, including conventional or immunotherapeutic reagents, is needed, and its development for canine use is crucial. The application of targeted systemic therapy for canines is receiving attention due to the success rate of immune checkpoint blockade therapy in humans58,59.
More importantly, even though canine lung cancers are infrequent, they can function as excellent comparative models for human NSCLC patients who have never smoked before. These human patients often have EGFR and ALK genetic mutations60,61. However, a few studies have shown that canine pulmonary adenocarcinomas do not show EGFR mutations or ALK alterations. Rather, in a study that analyzed 77 canine primary pulmonary carcinomas and 11 cell lines using whole-exome sequencing with selectively designed amplicons for 53 well-studied cancer genes, some commonly recurring mutated genes were included: HER2, TP53, PTEN, SMAD4, KRAS, VHL, and HRAS32. Therefore, although canine and human lung cancer models do share some clinical features, more studies need to be conducted to specify where there is biologic convergence and/or divergence to support molecular studies with targeted therapeutic agents in canine lung cancer patients for further validation in humans.
Bladder cancer
Bladder cancer, also known as urothelial carcinoma (UC) or transitional cell carcinoma (TCC), is another type of cancer that is also found in both humans and canines62,63. Bladder cancer is a frequently occurring cancer in both men and women and can be categorized into nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), with NMIBC comprising ~80% of all bladder cancer patients64. NMIBC patients tend to have a good prognosis since this type of tumor is hardly invasive. Nevertheless, MIBC tumors tend to invade beyond the epithelial layer into the muscle65; therefore, the identification of their molecular signatures and molecular drivers is crucial.
Studies have revealed that the histological, biological, and clinical attributes are similar between human and canine bladder cancer66,67,68. Bladder cancer in both species shares molecular targets such as EGFR, HER2, CDKN2A, CDKN2B, PIK3CA, BRCA2, and NF-κB16,69. In particular, EGFR, which is overexpressed in more than 70% of human bladder cancer, is also observed in the canine patient population. Due to these molecular similarities, dogs are great models for the study of biomarkers and the development of therapeutic drugs for bladder cancer68. In addition, coordinated differential expression of genes within cytogenetic bands occurs in canine bladder cancer, and these patterns are similar to those found in human bladder cancer66. It was discovered that genes with mutations in canine bladder cancer are more likely than nonmutated genes to be downregulated at the transcriptional level in the tumor66. Moreover, the tumors tend to invade neighboring urinary tract structures or metastasize to loco-regional and remote sites in humans and canines16. Occasionally, similar but different molecular mutations arise. For instance, canine invasive urothelial carcinoma presents a BRAFV595E mutation in 67–85% of cases, whereas human tumors harbor a BRAFV600E mutation70,71,72. In this context, some new mutations (FAM133B, RAB3GAP2, and ANKRD52) were found for canine bladder cancer66. However, even though different mutations were identified in the two species, the fact that many molecular targets are shared between the two species of bladder cancer is an important aspect of comparative oncological study.
Glioma
Intracranial gliomas are the most frequently occurring and one of the most lethal primary brain tumors in both humans and canines. In humans, gliomas are classified by progression, from low-grade (I–II) to high-grade (III–IV)73. Gliomas are one of the most frequently occurring brain tumors, especially in brachycephalic dog breeds74,75. Similar to humans, canines with gliomas display extremely poor survival despite various treatments ranging from chemotherapy radiation therapy to gene therapy76,77,78,79.
Studies on molecular alterations in GBM in humans have been investigated;80,81,82 the three main pathways involved are RTK/RAS/PI3K, RB, and p53 signaling83. Similar research has been conducted in canine gliomas, revealing genetic alterations in RTK/RAS/PI3K, RB, p53, CDKN2A, CDKN2B, and PDGFRA84. These genes and pathways are also found during human glioma genesis, revealing the similarities between human and canine glioma models85.
However, molecular phenotyping to differentiate human tumors based upon MGMT promoter methylation, mutation of IDH1 or IDH2 and chromosome 1p and 19q co-deletion has defined different prognostic subgroups, largely unrelated of histologic appearance, among human gliomas86,87. This is particularly relevant for human tumor samples that have a degree of mixed features and/or are complicated by insufficient and/or nonrepresentative sampling and provides avenues for targeted therapy development based upon molecular features.
Melanoma
Melanoma is the most commonly occurring type of skin cancer in humans, usually due to exposure to the sun and ultimately UV rays88,89. Canine melanoma, on the other hand, usually does not occur on the outer skin, as it is sun-protected by their coat. Rather, canine melanoma frequently occurs within oral cavities and nail beds90,91. The treatment of melanoma is still difficult, as chemotherapy is not effective; however, the recent development of targeted therapy and immunotherapy has improved the prognosis of melanoma patients92,93,94. Melanoma is usually treated with surgical resection in canines; however, aggressive melanoma treatment cannot depend solely on surgery since the rate of metastasis is too high90. As a result, similar to humans, systemic chemotherapy drugs are needed to minimize metastasis93.
Human and canine melanoma share numerous similarities, making dogs a decent preclinical model to study melanoma17,91. Canine melanomas have mutations in the RAS family members TP53, PTEN, MYC, MDM2, and CDKN2A95,96,97. Interestingly, these genes have also been found to be altered in human melanomas. Furthermore, NF1, BRAF, and KIT oncogenic mutations have also been discovered in both species. ERK and/or PI3K signaling activation has also been identified in human and canine melanomas98,99,100. Moreover, PD-L1 expression has been detected in both canine melanoma cell lines and patient-derived tumor tissues, further elucidating the potential for the use of checkpoint inhibitors and/or immunotherapies to be applied to canines, as in humans101,102. Therefore, canine models can be used as representative models of human melanoma, especially in the development of next-generation therapies103. These reports suggest that canine melanoma may be particularly sensitive to checkpoint inhibitory antibodies or other immunotherapeutic modalities as they become available, which may reflect the success of such agents in melanoma therapy in humans103,104.
Lymphoma
Lymphoma is a cancer of lymphocytes, which are immune cells that can usually be found in the lymph nodes, spleen, thymus, and bone marrow. Lymphoma can be categorized into two types: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma105. Lymphoma is found in both humans and canines, and multiple similarities exist, including cytogenetic and clinical features, pathology, tumor biology, tumor behavior, and genetic aberrations106,107. Consequently, canines can serve as an important animal model to study lymphoma and potential therapeutic options108,109,110.
One type of lymphoma is non-Hodgkin’s lymphoma (NHL), in which ~90% of cases are of B-cell origin in humans. On the other hand, the ratio of T-cell and B-cell lymphomas is 2:1 in canines, although there exists variance between breeds111,112. In a study involving a cohort of 608 canine lymphoma patients, 76% were found to have high-grade malignant lymphomas based on cytomorphological, histomorphological and immunological criteria and epidemiological and clinical data111.
Another type of lymphoma, diffuse large B-cell lymphoma (DLBCL), has been extensively studied in the canine model113,114,115. Gene expression profiling and immunohistochemistry analyses revealed that canine DLBCL has similar profiles to human DLBCL113. For example, NF-kB pathway genes are activated, and immunoglobulin heavy chain is altered113. Furthermore, germinal center and post-germinal center subtypes were identified in canine DLBCL, and these types showed different survival times; the findings in canines were consistent with DLBCL observations in humans113. In another study, gene expression profiles of 35 lymphoma samples in dogs were used to define three main groups: (1) low-grade T-cell lymphomas consisting exclusively of T-zone lymphomas; (2) high-grade T-cell lymphomas consisting of lymphoblastic T-cell lymphomas and peripheral T-cell lymphomas not otherwise specified; and (3) B-cell lymphomas consisting of marginal B-cell lymphomas, diffuse large B-cell lymphomas and Burkitt lymphomas116. The identified gene expression profiles were further categorized based on the expression of four genes related to lymphoma subtype and survival (CD28, ABCA5, CCDC3 and SMOC2)116. Moreover, a transcriptome comparison study based on RNA sequencing was performed with samples from 50 DLBCL patients and normal follicular B cells from 11 healthy dogs’ lymph nodes117. Transcripts involved in B-cell receptor (BCR), MYC signaling, the PI3K/AKT/mTOR pathway, DNA replication, and the cell cycle were significantly upregulated in DLBCL samples117. Furthermore, transcripts involved in the nuclear factor-κB (NF-κB) pathway (CD79, CD19, SYK, LYN, CARD11, BCL10, BTK, TRAF6, MYD88, NFKB2, TLR7, TLR9) were differentially expressed between DLBCL and normal samples117. Similar to these findings in canines, human DLBCL shows constitutive activation of NF-κB resulting from mutations in genes involved in this pathway117. These findings need further confirmation in larger cohorts of both humans and canines to evaluate the universal clinical utility of this comparative approach.
Leukemia
Leukemia is a cancer of white blood cells that begins in the bone marrow. Leukemia is another hematologic malignancy that is equally common in dogs and humans. Numerous genomic studies in canine leukemia have been performed, revealing that the mechanisms behind leukemogenesis are similar between canines and humans118. For instance, in both species, RB1 is deleted in chronic lymphocytic leukemia (CLL), and BCR-ABL is fused in chronic myeloid leukemia (CML)119. In more detail, the BCR-ABL tyrosine kinase translocation, which is called the “Raleigh chromosome” in canines and the “Philadelphia chromosome” in humans, is being used for categorizing additional subtypes and is utilized in monitoring cytogenetic remission in CMLs120,121,122. Additionally, in acute lymphoblastic leukemia (ALL)/acute undifferentiated leukemia (AUL) and chronic lymphocytic leukemia (CLL), increased expression of c-KIT was observed123, suggesting the use of tyrosine kinase inhibitors as a treatment option for canine leukemia patients, and this treatment is commonly used in human leukemia patients with tyrosine kinase-related aberrations.
Conclusion and perspectives
In this review, we explored several preclinical cancer models in both human and canine species that could be helpful for cancer research in terms of diagnosis, prognosis and treatment. Comparative medicine is a powerful tool and thus enables the development of novel therapeutic drugs. Currently, targeted therapies and personalized therapies are being actively developed, so the benefit of comparative medicine lies in that the selection of targets can be quickly and more easily made using animal targets. Through comparative medicine, researchers can identify new molecular targets, assess novel drugs, and identify which patient population would be fit for such novel therapies.
Numerous studies have been conducted to compare molecular profiles and tumor phenotypes in canine cancers and human cancers. Although further evaluation and clarification are necessary to associate canine cancers with human cancers, extensive studies have allowed the translation of diagnostic and prognostic markers to human oncology research. This review highlights the importance of canine models as ideal experimental models for studying and improving cancer treatments for humans.
References
Pruitt, K. Molecular and cellular changes during cancer progression resulting from genetic and epigenetic alterations. Prog. Mol. Biol. Transl. Sci. 144, 3–47 (2016).
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Seyfried, T. N., Flores, R. E., Poff, A. M. & D’Agostino, D. P. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35, 515–527 (2014).
Neophytou, C. M., Panagi, M., Stylianopoulos, T. & Papageorgis, P. The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers 13, 2053 (2021).
Dancey, J. E., Bedard, P. L., Onetto, N. & Hudson, T. J. The genetic basis for cancer treatment decisions. Cell 148, 409–420 (2012).
Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).
Wishart, D. S. Is cancer a genetic disease or a metabolic disease? EBioMedicine 2, 478–479 (2015).
Harris, H., Watkins, J. F., Campbell, G. L., Evans, E. P. & Ford, C. E. Mitosis in hybrid cells derived from mouse and man. Nature 207, 606–608 (1965).
Harris, H. & Watkins, J. F. Hybrid cells derived from mouse and man: artificial heterokaryons of mammalian cells from different species. Nature 205, 640–646 (1965).
Seyfried, T. N. & Shelton, L. M. Cancer as a metabolic disease. Nutr. Metab. 7, 7 (2010).
Seyfried, T. N. Cancer as a mitochondrial metabolic disease. Front. Cell Dev. Biol. 3, 43 (2015).
Shurin, M. R. et al. Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev. 25, 333–356 (2006).
Chakraborty, S. & Rahman, T. The difficulties in cancer treatment. Ecancermedicalscience 6, ed16 (2012).
Schiffman, J. D. & Breen, M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370, 20140231 (2015).
Dhawan, D., Hahn, N. M., Ramos-Vara, J. A. & Knapp, D. W. Naturally-occurring canine invasive urothelial carcinoma harbors luminal and basal transcriptional subtypes found in human muscle invasive bladder cancer. PLoS Genet. 14, e1007571 (2018).
Hernandez, B. et al. Naturally occurring canine melanoma as a predictive comparative oncology model for human mucosal and other triple wild-type melanomas. Int. J. Mol. Sci. 19, 394 (2018).
Onaciu, A. et al. Spontaneous and induced animal models for cancer research. Diagnostics 10, 660 (2020).
Davis, B. W. & Ostrander, E. A. Domestic dogs and cancer research: a breed-based genomics approach. ILAR J. 55, 59–68 (2014).
Paoloni, M. & Khanna, C. Translation of new cancer treatments from pet dogs to humans. Nat. Rev. Cancer 8, 147–156 (2008).
Son, K. H. et al. Integrative mapping of the dog epigenome: reference annotation for comparative inter-tissue and cross-species studies. Preprint at https://www.bioRxiv.org/content/10.1101/2022.07.22.501075v1 (2022).
Feng, Y. et al. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 5, 77–106 (2018).
McCart Reed, A. E. et al. Mixed ductal-lobular carcinomas: evidence for progression from ductal to lobular morphology. J. Pathol. 244, 460–468 (2018).
Lukasiewicz, S. et al. Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies—an updated review. Cancers 13, 4287 (2021).
Waks, A. G. & Winer, E. P. Breast cancer treatment: a review. JAMA 321, 288–300 (2019).
Sultan, F. & Ganaie, B. A. Comparative oncology: integrating human and veterinary medicine. Open Vet. J. 8, 25–34 (2018).
Hansen, K. & Khanna, C. Spontaneous and genetically engineered animal models; use in preclinical cancer drug development. Eur. J. Cancer 40, 858–880 (2004).
Sorenmo, K. U. et al. Canine mammary gland tumours; a histological continuum from benign to malignant; clinical and histopathological evidence. Vet. Comp. Oncol. 7, 162–172 (2009).
Varallo, G. R. et al. Prognostic phenotypic classification for canine mammary tumors. Oncol. Lett. 18, 6545–6553 (2019).
Kim, T. M. et al. Cross-species oncogenic signatures of breast cancer in canine mammary tumors. Nat. Commun. 11, 3616 (2020).
Lee, K. H., Hwang, H. J., Noh, H. J., Shin, T. J. & Cho, J. Y. Somatic mutation of PIK3CA (H1047R) is a common driver mutation hotspot in canine mammary tumors as well as human breast cancers. Cancers 11, 2006 (2019).
Lorch, G. et al. Identification of recurrent activating HER2 mutations in primary canine pulmonary adenocarcinoma. Clin. Cancer Res. 25, 5866–5877 (2019).
Seung, B. J., Cho, S. H., Kim, S. H., Lim, H. Y. & Sur, J. H. Quantitative analysis of HER2 mRNA expression by RNA in situ hybridization in canine mammary gland tumors: comparison with immunohistochemistry analysis. PLoS ONE 15, e0229031 (2020).
Nam, A. R. et al. Alternative methylation of intron motifs is associated with cancer-related gene expression in both canine mammary tumor and human breast cancer. Clin. Epigenetics 12, 110 (2020).
Jeong, S. J., Lee, K. H., Nam, A. R. & Cho, J. Y. Genome-wide methylation profiling in canine mammary tumor reveals miRNA candidates associated with human breast cancer. Cancers 11, 1466 (2019).
Lee, K. H., Shin, T. J., Kim, W. H. & Cho, J. Y. Methylation of LINE-1 in cell-free DNA serves as a liquid biopsy biomarker for human breast cancers and dog mammary tumors. Sci. Rep. 9, 175 (2019).
Lee, K. H., Park, H. M., Son, K. H., Shin, T. J. & Cho, J. Y. Transcriptome signatures of canine mammary gland tumors and its comparison to human breast cancers. Cancers 10, 317 (2018).
Park, H. M. et al. Common plasma protein marker LCAT in aggressive human breast cancer and canine mammary tumor. BMB Rep. 53, 664–669 (2020).
Rawla, P. Epidemiology of prostate cancer. World J. Oncol. 10, 63–89 (2019).
Laufer-Amorim, R. et al. Comprehensive genomic profiling of androgen-receptor-negative canine prostate cancer. Int. J. Mol. Sci. 20, 1555 (2019).
Christensen, B. W. Canine prostate disease. Vet. Clin. North Am. Small Anim. Pract. 48, 701–719 (2018).
Leroy, B. E. & Northrup, N. Prostate cancer in dogs: comparative and clinical aspects. Vet. J. 180, 149–162 (2009).
Iizuka, K. et al. Comparison of outcomes between medical and surgical treatment in dogs with prostatic adenocarcinoma: a retrospective study. BMC Vet. Res. 18, 36 (2022).
Baek, S. J., McEntee, M. F. & Legendre, A. M. Review paper: Cancer chemopreventive compounds and canine cancer. Vet. Pathol. 46, 576–588 (2009).
Ryman-Tubb, T. et al. Comparative pathology of dog and human prostate cancer. Vet. Med. Sci. 8, 110–120 (2022).
Davey, R. A. & Grossmann, M. Androgen receptor structure, function and biology: from bench to bedside. Clin. Biochem. Rev. 37, 3–15 (2016).
Takayama, K. & Inoue, S. Transcriptional network of androgen receptor in prostate cancer progression. Int. J. Urol. 20, 756–768 (2013).
Fujita, K. & Nonomura, N. Role of androgen receptor in prostate cancer: a review. World J. Mens. Health 37, 288–295 (2019).
Formaggio, N., Rubin, M. A. & Theurillat, J. P. Loss and revival of androgen receptor signaling in advanced prostate cancer. Oncogene 40, 1205–1216 (2021).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 162, 454 (2015).
Leung, J. K. & Sadar, M. D. Non-genomic actions of the androgen receptor in prostate cancer. Front. Endocrinol. 8, 2 (2017).
Lin, H. Y. & Palmieri, C. Is STAT3 and PTEN expression altered in canine prostate cancer? J. Comp. Pathol. 155, 185–189 (2016).
Leis-Filho, A. F. et al. Expression and prognostic significance of vascular endothelial growth factor-A (VEGF-A) and its receptor in canine prostate cancer. Prostate 81, 1021–1031 (2021).
Nicholson, A. G. et al. The 2021 WHO Classification of lung tumors: impact of advances since 2015. J. Thorac. Oncol. 17, 362–387 (2022).
Raso, M. G., Bota-Rabassedas, N. & Wistuba, I. I. Pathology and classification of SCLC. Cancers 13, 820 (2021).
Hifumi, T., Miyoshi, N., Kawaguchi, H., Nomura, K. & Yasuda, N. Immunohistochemical detection of proteins associated with multidrug resistance to anti-cancer drugs in canine and feline primary pulmonary carcinoma. J. Vet. Med. Sci. 72, 665–668 (2010).
Lee, B. M., Clarke, D., Watson, M. & Laver, T. Retrospective evaluation of a modified human lung cancer stage classification in dogs with surgically excised primary pulmonary carcinomas. Vet. Comp. Oncol. 18, 590–598 (2020).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Dafni, U., Tsourti, Z., Vervita, K. & Peters, S. Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. Lung Cancer 134, 127–140 (2019).
D’Arcangelo, M., D’Incecco, A. & Cappuzzo, F. Rare mutations in non-small-cell lung cancer. Future Oncol. 9, 699–711 (2013).
Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).
Higuchi, T. et al. Characterization and treatment of transitional cell carcinoma of the abdominal wall in dogs: 24 cases (1985-2010). J. Am. Vet. Med. Assoc. 242, 499–506 (2013).
Park, J. C. & Hahn, N. M. Bladder cancer: a disease ripe for major advances. Clin. Adv. Hematol. Oncol. 12, 838–845 (2014).
Zhu, S., Yu, W., Yang, X., Wu, C. & Cheng, F. Traditional classification and novel subtyping systems for bladder cancer. Front. Oncol. 10, 102 (2020).
Kobayashi, T. Understanding the biology of urothelial cancer metastasis. Asian J. Urol. 3, 211–222 (2016).
Ramsey, S. A. et al. Cross-species analysis of the canine and human bladder cancer transcriptome and exome. Genes Chromosomes Cancer 56, 328–343 (2017).
de Brot, S. et al. The dog as an animal model for bladder and urethral urothelial carcinoma: comparative epidemiology and histology. Oncol. Lett. 16, 1641–1649 (2018).
Knapp, D. W. et al. Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development. ILAR J. 55, 100–118 (2014).
Shapiro, S. G. et al. Canine urothelial carcinoma: genomically aberrant and comparatively relevant. Chromosome Res. 23, 311–331 (2015).
Decker, B. et al. Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer-evidence for a relevant model system and urine-based diagnostic test. Mol. Cancer Res. 13, 993–1002 (2015).
Mochizuki, H. & Breen, M. Comparative aspects of BRAF mutations in canine cancers. Vet. Sci. 2, 231–245 (2015).
Mochizuki, H., Kennedy, K., Shapiro, S. G. & Breen, M. BRAF mutations in canine cancers. PLoS ONE 10, e0129534 (2015).
Omuro, A. & DeAngelis, L. M. Glioblastoma and other malignant gliomas: a clinical review. JAMA 310, 1842–1850 (2013).
Jose-Lopez, R. et al. Clinical features, diagnosis, and survival analysis of dogs with glioma. J. Vet. Intern. Med. 35, 1902–1917 (2021).
Merickel, J. L., Pluhar, G. E., Rendahl, A. & O’Sullivan, M. G. Prognostic histopathologic features of canine glial tumors. Vet. Pathol. 58, 945–951 (2021).
Pluhar, G. E. et al. Anti-tumor immune response correlates with neurological symptoms in a dog with spontaneous astrocytoma treated by gene and vaccine therapy. Vaccine 28, 3371–3378 (2010).
Boudreau, C. E. et al. Intratumoral delivery of STING agonist results in clinical responses in canine glioblastoma. Clin. Cancer Res. 27, 5528–5535 (2021).
Miller, A. D., Miller, C. R. & Rossmeisl, J. H. Canine primary intracranial cancer: a clinicopathologic and comparative review of glioma, meningioma, and choroid plexus tumors. Front. Oncol. 9, 1151 (2019).
Hidalgo Crespo, E., Farre Marine, A., Pumarola, I. B. M., Borrego Masso, J. F. & Lujan Feliu-Pascual, A. Survival time after surgical debulking and temozolomide adjuvant chemotherapy in canine intracranial gliomas. Vet. Sci. 9, 427 (2022).
Lai, W., Li, D., Kuang, J., Deng, L. & Lu, Q. Integrated analysis of single-cell RNA-seq dataset and bulk RNA-seq dataset constructs a prognostic model for predicting survival in human glioblastoma. Brain Behav. 12, e2575 (2022).
Rajaraman, P. et al. Genome-wide association study of glioma and meta-analysis. Hum. Genet. 131, 1877–1888 (2012).
Couturier, C. P. et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat. Commun. 11, 3406 (2020).
Han, S. et al. Alterations in the RTK/Ras/PI3K/AKT pathway serve as potential biomarkers for immunotherapy outcome of diffuse gliomas. Aging 13, 15444–15458 (2021).
Dickinson, P. J. et al. Chromosomal aberrations in canine gliomas define candidate genes and common pathways in dogs and humans. J. Neuropathol. Exp. Neurol. 75, 700–710 (2016).
Colardo, M., Segatto, M. & Di Bartolomeo, S. Targeting RTK-PI3K-mTOR axis in gliomas: an update. Int. J. Mol. Sci. 22, 4899 (2021).
Kramar, F. et al. IDH1/2 mutation and MGMT promoter methylation—the relevant survival predictors in Czech patients with brain gliomas. Folia Biol. 62, 194–202 (2016).
Mizoguchi, M. et al. Molecular characteristics of glioblastoma with 1p/19q co-deletion. Brain Tumor Pathol. 29, 148–153 (2012).
Sample, A. & He, Y. Y. Mechanisms and prevention of UV-induced melanoma. Photodermatol. Photoimmunol. Photomed. 34, 13–24 (2018).
Sun, X., Zhang, N., Yin, C., Zhu, B. & Li, X. Ultraviolet radiation and melanomagenesis: from mechanism to immunotherapy. Front. Oncol. 10, 951 (2020).
Nishiya, A. T. et al. Comparative aspects of canine melanoma. Vet. Sci. 3, 7 (2016).
Simpson, R. M. et al. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma. Pigment Cell Melanoma Res. 27, 37–47 (2014).
Deacon, D. C., Smith, E. A. & Judson-Torres, R. L. Molecular biomarkers for melanoma screening, diagnosis and prognosis: current state and future prospects. Front. Med. 8, 642380 (2021).
Fonseca-Alves, C. E. et al. Current status of canine melanoma diagnosis and therapy: report from a colloquium on canine melanoma organized by ABROVET (Brazilian Association of Veterinary Oncology). Front. Vet. Sci. 8, 707025 (2021).
Shtivelman, E. et al. Pathways and therapeutic targets in melanoma. Oncotarget 5, 1701–1752 (2014).
Hendricks, W. P. D. et al. Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis. PLoS Genet. 14, e1007589 (2018).
Prouteau, A. & Andre, C. Canine melanomas as models for human melanomas: clinical, histological, and genetic comparison. Genes 10, 501 (2019).
Wong, K. et al. Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma. Nat. Commun. 10, 353 (2019).
Wei, B. R. et al. Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma. Pigment Cell Melanoma Res. 29, 643–655 (2016).
Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017).
Fowles, J. S., Denton, C. L. & Gustafson, D. L. Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma. Vet. Comp. Oncol. 13, 288–304 (2015).
Hartley, G. et al. Immune regulation of canine tumour and macrophage PD-L1 expression. Vet. Comp. Oncol. 15, 534–549 (2017).
Maekawa, N. et al. PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanoma. NPJ Precis. Oncol. 5, 10 (2021).
Stevenson, V. B., Perry, S. N., Todd, M., Huckle, W. R. & LeRoith, T. PD-1, PD-L1, and PD-L2 gene expression and tumor infiltrating lymphocytes in canine melanoma. Vet. Pathol. 58, 692–698 (2021).
Maekawa, N. et al. Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy. Sci. Rep. 12, 9265 (2022).
Jiang, M., Bennani, N. N. & Feldman, A. L. Lymphoma classification update: T-cell lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms. Expert Rev. Hematol. 10, 239–249 (2017).
Seelig, D. M., Avery, A. C., Ehrhart, E. J. & Linden, M. A. The comparative diagnostic features of canine and human lymphoma. Vet. Sci. 3, 11 (2016).
Ito, D., Frantz, A. M. & Modiano, J. F. Canine lymphoma as a comparative model for human non-Hodgkin lymphoma: recent progress and applications. Vet. Immunol. Immunopathol. 159, 192–201 (2014).
Dias, J. N. R. et al. Immunotherapeutic strategies for canine lymphoma: changing the odds against non-Hodgkin lymphoma. Front. Vet. Sci. 8, 621758 (2021).
McDonald, J. T. et al. Comparative oncology DNA sequencing of canine T cell lymphoma via human hotspot panel. Oncotarget 9, 22693–22702 (2018).
Marconato, L., Gelain, M. E. & Comazzi, S. The dog as a possible animal model for human non-Hodgkin lymphoma: a review. Hematol. Oncol. 31, 1–9 (2013).
Ponce, F. et al. A morphological study of 608 cases of canine malignant lymphoma in France with a focus on comparative similarities between canine and human lymphoma morphology. Vet. Pathol. 47, 414–433 (2010).
Harris, L. J. et al. Clinical features of canine nodal T-cell lymphomas classified as CD8+ or CD4-CD8- by flow cytometry. Vet. Comp. Oncol. 18, 416–427 (2020).
Richards, K. L. et al. Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL. Cancer Res. 73, 5029–5039 (2013).
Giannuzzi, D. et al. Mutational landscape of canine B-cell lymphoma profiled at single nucleotide resolution by RNA-seq. PLoS ONE 14, e0215154 (2019).
Ferraresso, S. et al. DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine diffuse large B-cell lymphoma. Sci. Rep. 7, 11591 (2017).
Frantz, A. M. et al. Molecular profiling reveals prognostically significant subtypes of canine lymphoma. Vet. Pathol. 50, 693–703 (2013).
Aresu, L. et al. New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease. Haematologica 104, e256–e259 (2019).
Avery, A. C. The genetic and molecular basis for canine models of human leukemia and lymphoma. Front. Oncol. 10, 23 (2020).
Breen, M. & Modiano, J. F. Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans-man and his best friend share more than companionship. Chromosome Res. 16, 145–154 (2008).
Culver, S. et al. Molecular characterization of canine BCR-ABL-positive chronic myelomonocytic leukemia before and after chemotherapy. Vet. Clin. Pathol. 42, 314–322 (2013).
Figueiredo, J. F., Culver, S., Behling-Kelly, E., Breen, M. & Friedrichs, K. R. Acute myeloblastic leukemia with associated BCR-ABL translocation in a dog. Vet. Clin. Pathol. 41, 362–368 (2012).
Perez, M. L. et al. Partial cytogenetic response with toceranib and prednisone treatment in a young dog with chronic monocytic leukemia. Anticancer Drugs 24, 1098–1103 (2013).
Giantin, M. et al. Evaluation of tyrosine-kinase receptor c-KIT (c-KIT) mutations, mRNA and protein expression in canine leukemia: might c-KIT represent a therapeutic target? Vet. Immunol. Immunopathol. 152, 325–332 (2013).
Acknowledgements
This work was supported by the Brain Korea 21 Project for Veterinary Science, Seoul National University, and the Basic Science Research Program through the National Research Foundation (NRF) funded by the ICT of the Korean government (MSIT) [NRF-2021R1A5A1033157 for SRC program: Comparative Medicine Disease Research Center (CDRC)].
Author information
Authors and Affiliations
Contributions
J.H.O. conceived of the article, performed literature search, data collection, and drafted the manuscript. J-Y. C. critically revised and supervised the work. All authors modified and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Oh, J.H., Cho, JY. Comparative oncology: overcoming human cancer through companion animal studies. Exp Mol Med 55, 725–734 (2023). https://doi.org/10.1038/s12276-023-00977-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s12276-023-00977-3
