A review of spontaneous bone metastases in domestic and laboratory animals.

Introduction

Bone is one of the preferential sites of metastasis for some cancers. Bone metastases commonly affect patients with advanced cancers, most notably solid tumors originating in the breast, prostate, thyroid, lung, kidney, and in those with multiple myeloma [1] . Bone metastases are more prevalent than primary bone tumors and can be classified into osteolytic, osteoblastic, or mixed phenotypes based on the appearance of the lesions using advanced imaging (radiography, computed tomography (CT)) [2] . Owing to the high prevalence of bone metastases and the substantial morbidity associated with disease progression, animal models of bone metastasis that mimic distinct stages of the human disease are of great importance in investigating tumor-bone interactions.

Numerous experimental animal models of metastasis, primarily using rodents, have been developed, including chemically- or genetically-induced cancer models and xenograft models of human and animal cancers (extensively reviewed in the literature) [3] , [4] , [5] . Rodents have greatly contributed to our understanding of bone metastasis pathophysiology and mechanism and are ideal experimental animal models due their genotypic malleability, availability, and reproducibility. However, experimental models frequently do not adequately represent several characteristic features of bone metastases in humans, such as long latency periods, significant cancer cell heterogeneity, complex interactions with the immune system, induction of bone formation in the context of osteoblastic metastases, and translational outcomes of therapies.

Less is known about the prevalence of spontaneous bone metastasis across solid tumors in animal species. The study of spontaneous bone metastases in animals, especially in companion animals, provides a distinct and complementary perspective from that generated with approaches using more traditionally used laboratory animals and growing use of new approach methodologies (NAMs). Selected clinical reports of animals with spontaneous bone metastases are summarized in Table 1 .

Several companion and laboratory animals, namely dogs, mice, and ferrets, have spontaneous cancer prevalences that equal or surpass that observed in humans, particularly after factoring in lifespan and the total numbers of cells that could undergo cancer-inducing mutations [ 24 ]. The cancer incidence rate in dogs is roughly 2-10x that of humans [ [25] , [26] , [27] ]. Studies in purebred dogs have identified specific cancer-associated mutations relevant to human health [ [28] , [29] , [30] ]. Companion animals can be exposed to similar environmental factors as their owner (cancer “sentinels”), can be of comparable anatomic skeletal size in some cases, and provide a background of genetic diversity that parallels humans, even more so in mixed breeds when compared to pure breed animals [ 31 ]. In addition, companion animals have intact immune systems for evaluating not only the host immune response but more importantly for testing immune-based treatments, a rapidly expanding field in human oncology.

Comparative and translational cancer research benefits both animal and human patients, as well as accelerate the clinical evaluation of the most promising technologies and strategies . Bone metastasis research can benefit significantly from a One Health approach that engages the growing companion animal population. This current review describes the natural history of animals with spontaneous bone metastasis and provides information on the successes and challenges of working with companion animals in translational research.

Canine

Canine and human physiology closely resembles each other. From this, there is a high degree of overlap in the disease spectrum and their response to treatment between these two species. It has since been demonstrated that the present-day dog has distinct advantages when compared to other model systems for identifying and mapping genes implicated in human disease [ 32 ]. Spontaneous cancers in dogs often recapitulate the biology and heterogeneity of the human disease, including complex interactions between the immune system and tumor cells, development of chemotherapy resistance, and metastases ultimately resulting in patient death [ 33 ]. Studies have reported the detection of bone metastases and the observations of similar radiographic and histopathologic phenotypes in dogs with various types of cancer ( Fig. 1 ) [ [10] , [34] , [35] , [36] ]. From our clinical perspective, dogs do not develop bone metastases as frequently as humans. Metastasis to, or secondary involvement of, bone occurs in approximately 11–17% of malignant canine neoplasms [ [10] , [37] ]. However, subclinical and oligometastatic bone metastasis may go undetected due to the limited use of advanced imaging and tumor-specific tracers in dogs and other companion animals. But like in humans, most bone-metastatic tumors in dogs are carcinomas and primarily originate from the mammary gland, urogenital system, and lung [ [10] , [35] , [37] , [38] ]( Table 2 ). Less commonly, bone metastasis occurs secondary to hepatocellular carcinoma, cholangiocellular carcinoma, ovarian carcinoma, thyroid carcinoma, and carcinomas of the gastrointestinal tract [ [10] , [17] , [35] , [38] , [39] ]. Hemangiosarcoma and osteosarcoma are more common types of bone-metastatic mesenchymal tumors [ [10] , [35] , [40] ].

Prostate cancer

The dog is the only species other than man to spontaneously develop benign prostatic hyperplasia, prostatitis, prostate carcinoma (PCa), and subsequent bone metastases [ 48 ]. PCa is rare in other domestic animals and nonhuman primates [ 49 ]. Unlike PCa in men, which is common and often latent, PCa in dogs is relatively uncommon but typically aggressive and metastatic, with a reported prevalence of 0.2% to 0.6% based on post-mortem evaluation [ 50 ]. The prevalence of PCa in canines increases with age, with a mean age of 9.9 years old at diagnosis [ 51 ]. PCa in dogs has a similar or increased prevalence in neutered dogs when compared to intact dogs [ [52] , [53] , [54] ], and unlike in man, is usually androgen-independent, at least by the time of clinical presentation.

The cell of origin of canine PCa has not been definitively determined, but molecular studies have revealed they may arise from prostatic ductular epithelium rather than the prostatic acini as occurs in men [ [41] , [55] , [56] , [57] , [58] ]. A significant difference between PCa in men and dogs is the role of androgens [ 58 ]. The androgen signaling pathway is important for the development of human PCa, and approximately 80% of patients are have cancers that are initially androgen-dependent, which makes androgen-deprivation therapy an effective strategy for the control of PCa in men [ 59 ]. However, PCa in dogs usually has low or absent expression of the androgen receptor in their tumor cells [ [56] , [60] ]. In addition, some studies reported an increased risk of PCa in neutered dogs when compared to intact dogs [ [51] , [52] , [53] ]. Therefore, PCa in dogs is a good model for late-stage, androgen pathway independent PCa. The majority of intact dogs will develop benign prostatic hyperplasia (BPH) as they age [ [61] , [62] ]. The occurrence of high-grade prostatic intraepithelial neoplasia (HGPIN) is debated in dogs [ [63] , [64] , [65] ], and therefore may not be a precursor lesion as in men. Due to the aggressive nature of canine PCa, most dogs present with advanced disease, exhibiting significant local invasion and widespread metastases. The metastatic rate at diagnosis is approximately 40% and up to 80% at death, with spread primarily to lymph nodes (51%), lungs (50%), and bone (22–25%)[ [6] , [41] ]. Intramedullary bone metastases are predominantly mixed or osteolytic, although up 25% have had an osteoblastic phenotype [ 6 ]. Clinical signs of PCa bone metastases in dogs include bone pain, posterior paresis and/or paralysis, and pathological fractures. Diagnosis of bone metastasis typically involves radiography, computed tomography (CT), magnetic resonance imaging (MRI), or histological examination of the afflicted bones.

The prognosis of primary PCa in dogs is poor due to the lack of reliable screening methods. The kallikrein serine protease, prostate-specific antigen (PSA), commonly used for early detection and monitoring in human PCa, is not used in dogs due to the lack of its expression [ 66 ]. Canine prostate-specific arginine esterase (CPSE), the most abundant kallikrein present in the prostatic secretions of dogs, is not specific to, nor elevated in, canine PCa [ [66] , [67] ]. Therefore, PCa in dogs is often advanced at diagnosis and has a poor prognosis. Effective treatment is therefore limited. With no detectable metastases, surgery and medical treatments, including total prostatectomy and adjuvant non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy, may help relieve clinical signs and prolong survival in dogs [ [68] , [69] ]. Treatment with medical therapy alone (NSAIDs and chemotherapy) has resulted in a median survival of 90.5–106 days [ [70] , [71] ]. A retrospective study revealed surgery alone was superior to medical management, with the surgery-only group having a median survival time of 337 days [ 70 ]. However, when cancer cells have metastasized, euthanasia is necessary once the quality of life has deteriorated, or clinical signs cannot be controlled.

RNA-sequencing of canine PCa compared with nonmalignant prostate tissues showed that differentially expressed genes were enriched in five super-pathways, including inflammatory response and cytokines, regulation of the immune system and cell death, cell surface and PI3K signaling, cell cycle, and phagosome and autophagy [ 72 ]. In recent years, several canine PCa cell lines have been established from dogs with spontaneous PCa from our laboratory and others, including Ace-1 [ 73 ], Leo [ 74 ], Probasco [ 75 ], LuMa [ 76 ], and DPC-1 [ 77 ]. These cell lines metastasize to bone in nude mice after intracardiac injection and subsequently induce mixed or osteoblastic lesions dependent, in part, to WNT signaling, a known pathway in osteoblastic bone metastasis in men [ [78] , [79] , [80] ]. These findings importantly demonstrate that canine PCa induces a similar bone phenotype through shared mechanisms as observed in to other rodent experimental and human clinical disease [5] .

Mammary cancer

Female dogs are susceptible to both benign and malignant mammary tumors, with the annual incidence being twice as high in dogs when compared to women [ 81 ]. Malignant canine mammary tumors can be histologically categorized into carcinomas, sarcomas, or mixed types, with the majority being carcinomas [ 82 ]. The proportion of benign to malignant mammary tumors is roughly 1:1 in adult dogs, although this ratio can change based on regional practices of ovariohysterectomy (spaying) [ [83] , [84] , [85] ]. A landmark veterinary study found female dogs spayed before one estrous cycle or after 2 or more estrous cycles had relative risks of 0.5% and 26%, respectively, of developing mammary carcinomas when compared to dogs who were never spayed [ 86 ]. Thus, even spaying after two estrus cycles resulted in a 74% reduction in risk of mammary tumor development when compared to intact dogs. Spaying, even if performed after two years of age, associated with a 4-fold decrease in risk of dying from a malignant mammary tumor in a later study [ 87 ]. A breed predisposition to mammary tumors is not definitive, but several studies have found increased risk of developing malignant tumors in purebred dogs, specifically spaniels, boxer dogs, German shepherds, and Labrador retrievers [ [88] , [89] , [90] ].

The prognosis for canine malignant mammary tumors following diagnosis depends on the stage and histologic type, with one study finding a post-surgical survival time of only 6 months with higher grade tumors [ [91] , [92] ]. One study found Approximately 30% of canine malignant mammary tumors metastasize to local lymph nodes, subsequently leading to distant metastases, which are commonly observed in the lungs and occasionally in bones [ 93 ]. This clinical progression shares similarities with human breast cancer, where approximately 7% of women present with metastatic disease, and 20% of those with localized disease eventually develop metastatic lesions across all breast cancer subtypes [ 94 ]. Survey studies demonstrated that bone metastases in dogs are most commonly caused by mammary carcinomas, representing 12–38% of all primary tumors with bone metastases [ [10] , [34] , [35] , [38] ]. Canine mammary carcinoma bone metastases frequently appear as multiple foci in several bones, with the humeri, femora, and thoracic and lumbar vertebrae being the most affected sites [ 10 ]. Histological analyses reveal that osteolytic metastases are predominant in most cases, characterized by focally extensive areas of bone loss.

The development of canine mammary carcinoma is hormone-dependent and can exhibit dysregulated expression of HER2 , BRCA1 , BRCA2 , and TP53 , as observed in human breast cancer [ [95] , [96] , [97] ]. Investigations into gene expression signatures in metastatic canine mammary carcinoma have revealed comparable expression patterns between dog and human cases. Upregulated genes are associated with cell cycle regulation, DNA damage repair, matrix modulation, protein folding, and proteasomal degradation [ 98 ]. Conversely, downregulated genes are linked to cell differentiation, growth factor pathways, focal adhesion pathways, and regulators of actin organization [ 98 ]. These findings have also been identified at the protein level — those related to proliferation, cell motility, and resistance to hypoxia are highly expressed in metastatic carcinoma when compared to their non-metastatic counterparts [ 99 ].

Urothelial (transitional cell) carcinoma

Urothelial carcinoma (UC) represents the most prevalent form of urogenital cancer in dogs, accounting for approximately 2% of all canine malignancies [ 42 ]. UC typically occurs in older dogs [ 41 ]. Canine UC demonstrates both sex and breed predisposition. The incidence in female dogs is higher than in male dogs (ranging 1.71 to 1.95:1) and the risk is further enhanced in neutered dogs [ 100 ]. Breeds such as Scottish terriers, eskimo dogs, Shetland Sheepdogs, West Highland white terriers, keeshonds, samoyeds, and beagles are more susceptible to UC [ 100 ].

UC predominately occurs in the trigone region of the bladder and has also been reported to involve the urethra and prostate in male dogs [ 101 ]. Canine UC is generally characterized as a high-grade invasive cancer [ 102 ]. Nodal and distant metastases are present in approximately 20% of cases at diagnosis and are found in more than 50% of cases at death [ 100 ]. A retrospective study of 137 dogs with UC revealed that 58% of cases had distant metastases at autopsy, with lungs (50.0%), bones (11.0%), and liver (7.0) being the most affected sites [ 42 ]. A similar study of muscle-invasive UC in 367 people found that 68% had metastasis, with bone involvement in 32% of cases [ 103 ]. Bone metastases in dogs have been detected by CT and histologically confirmed in vertebrae, appendicular bones, pelvis, ribs, and the cranium [ 8 ]. The resultant phenotypes were aggressive osteolytic bone metastases in most cases with few osteoblastic metastases, mirroring the bone phenotype in humans [ 8 ]. Clinical signs of canine UC in dogs often include dysuria, urinary incontinence, and/or hematuria due to partial or complete urinary tract obstruction subsequent to papillary lesions and a thick bladder wall, which can persist for weeks to months prior to diagnosis [ 102 ]. Less commonly, dogs have lameness caused by bone metastasis or hypertrophic osteopathy [ 102 ].

Renal cell carcinoma

Primary renal cancer occurs infrequently in dogs, with a prevalence of 0.3% to 2% among all canine neoplasms [ [44] , [104] ]. Renal cell carcinoma (RCC) is the most common type and is thought to originate from cells of the proximal convoluted tubules [ 105 ]. Dogs affected with RCC are typically middle-aged or older, with an average age of 8 years old at diagnosis, and the male-to-female ratio is 1.8:1 [ 43 ], which is similar to 2:1 in humans [ 106 ].

Canine renal cancer of all types is aggressive, with a high metastatic rate. One study in dogs with primary renal cancers reported a metastatic rate of 69% for carcinomas, 88% for sarcomas, and 75% for nephroblastomas, with metastatic lesions occurring in the contralateral kidney, spleen, and liver [ 105 ]. In humans, bone is the second most common site of metastasis of RCC following the lung [ 107 ]. Bone metastases in canine RCC have been observed in only a few cases. Here, RCC bone metastases were detected in the thoracic vertebrae, ribs, femora, and tibiae, with obvious osteolytic bone lesions [ [9] , [43] , [108] ]. Dogs with RCC bone metastases will experience joint swelling, bone pain, and even tetraparalysis. Hypertrophic osteopathy secondary to primary RCC has been reported in dogs [ 9 ].

Lung cancer

In humans, most lung cancers are carcinomas and histologically classified as small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), which exhibit distinct biological behaviors, clinical courses, and responses to therapy [ [109] , [110] ]. Bone metastasis occurs in a significant proportion of human lung cancer patients, ranging from 30% to 40% [ 111 ]. Most lung cancer bone metastases are either osteolytic (SCLC) or a combination of osteolytic and osteoblastic (NSCLC) [ [112] , [113] ]. In dogs, metastatic cancers to the lung are more commonly observed than primary lung cancers. Primary lung cancers in dogs account only for 2–4 dogs per ten thousand within the pet population [ 114 ]. Boxer dogs, Bernese mountain dogs, and Doberman pinschers may be predisposed to pulmonary carcinomas [ 115 ]. The average age of diagnosis in dogs is around 10–11 years [ [114] , [115] ]. While the relationship between cigarette smoking and the increased incidence of lung cancer has been established in humans, no apparent environmental factors have been identified in dogs. Primary lung cancer has moderate to high potential for metastasis, and metastasis affects other lung lobes, lymph nodes, pleura, bones, and the brain [ 114 ]. Cases of lung cancer bone metastasis in dogs were mixed lesions in the humerus, femurs, ribs, pubis, and vertebrae [ 10 ].

Osteosarcoma

Osteosarcoma (OSA) is the most commonly diagnosed primary bone neoplasm in both dogs and humans and often induces osteolysis of pre-existing bone [ 116 ]. OSA more commonly affects dogs, with a reported incidence of 13.9/100,000 in dogs when compared to 1.02/100,000 in people [ 117 ]. Dogs classified as large or giant breeds such as rottweilers, Irish wolfhounds, greyhounds, and great Danes have a much higher risk of developing OSA [ [117] , [118] ]. In these breeds, OSA can be observed in juvenile and geriatric dogs; a bimodal distribution is also observed in humans, although with a greater relative prevalence in younger populations when compared to dogs [ 119 ]. OSA has a high metastatic rate to lungs, but bones and lymph nodes are also occasionally affected [ 120 ]. Eighty percent of dogs with OSA die with lung metastasis [ 116 ]. Bone metastasis (bone-to-bone metastasis; Fig. 2 ) has also been reported in several studies [ [10] , [37] , [40] ]. In addition, the original location of OSA affects the risk of metastases and mortality. Tumors localized at the distal radius are associated with a lower risk of metastasis, while tumors localized at the proximal humerus and distal femur or proximal tibia have a higher metastatic rate, which results in a significant increase in mortality [ 121 ]. Typical clinical signs are lameness and local swelling at the tumor site due to extension of the tumors into the surrounding soft tissues [ [122] , [123] ].

Thyroid cancer

Thyroid cancer (TC) is the most prevalent endocrine tumor in both humans and dogs, with an increasing risk in older patients [ 124 ]]. Malignant epithelial cells that originate from follicular cells of the human thyroid gland are histologically classified as papillary, follicular, or anaplastic [ 125 ]. Papillary thyroid cancer (PTC) is the most common type in humans and one of the most treatable cancers compared with other malignant subtypes [ 126 ]. Canine TC can be derived from follicular (non-medullary) or C-cells (medullary), with follicular thyroid carcinoma (FTC) being the most frequent type of canine TC [ [47] , [127] ]. TC has an obvious sex predisposition in humans as women are three times more afflicted than men [ 124 ]. The prevalence of TC is equally between sexes in dogs [ [47] , [128] ]. Breed predilection of canine TC remains controversial. Boxers, beagle dogs, golden retrievers, Shetland sheepdogs, old English sheepdogs, and Cairn terriers, have been shown to be more susceptible to TC, but results are inconsistent among different studies [ [46] , [129] , [130] , [131] ].

Lung and bone are the primary sites of TC distant metastasis in people. Bone is involved in approximately 45% of TC with distant metastasis [ 132 ]. Between 2–15% of TC will metastasize to the skeleton, most commonly affecting the vertebrae (29%), pelvis (22%), ribs (17%), and femur (11%) [ [133] , [134] ]. Osteolysis is the predominant phenotype, with osteoblastic lesions occasionally observed [ 135 ]. TC in dogs also primarily metastasizes to the lungs. Pulmonary metastasis was detected in 38% of dogs with FTC at the time of diagnosis using thoracic radiographs [ 46 ]. Reports of bone metastasis are rare for both canine follicular and medullary thyroid carcinomas [ [11] , [12] ]. When combining data from multiple survey studies investigating bone metastasis in canine tumors, only 1/133 (0.75%) cases of bone metastasis were due to TC [ [10] , [34] , [35] , [37] , [38] ].

Feline

Domestic cats naturally develop benign and malignant neoplasms, albeit less frequently than in dogs [ 136 ]. Like dogs, cats experience the same environmental risk factors and exhibit considerable genomic homology with humans. Cats may serve as valuable models for specific cancers, such as breast (mammary) carcinoma, lung carcinoma, and oral squamous cell carcinoma, due to the increased incidence in this species [ [5] , [137] , [138] , [139] ]. In general, bone metastasis is infrequent in cats, with most bone lesions being osteolytic.

Mammary cancer

Feline mammary tumors are the third most common tumor type in cats and primarily diagnosed at 10–12 years of age [ [140] , [141] , [142] ]. Most mammary tumors in cats are malignant, with up to 86% being carcinomas [ 143 ]. There is a breed predisposition in purebred Siamese cats, which are more likely to develop mammary tumors at a younger age than other cat breeds [ [142] , [144] ] This gives strong support for genetic factors leading to the development of mammary cancer in this breed of cat. Feline mammary cancer is characterized by their clinical and histological aggressiveness and subsequent systemic progression. The neoplasms are typically invasive adenocarcinomas or ductal carcinomas that have a high incidence of recurrence after surgical removal [4] . These tumors have low levels of estrogen and progesterone receptor expression and are not hormonally dependent as observed in women [ 145 ]. Reported metastatic rates range from 50% to 90%, with the most affected sites being regional lymph nodes, lungs, liver, and pleura [ 146 ]. Bone metastases are uncommon in published cases [ 19 ].

Lung cancer

In cats, primary pulmonary carcinomas originate from the lung epithelia and are infrequent, accounting for only 0.69% to 0.75% of all postmortem examination diagnoses [ [147] , [148] ]. An analysis of 39 spontaneous feline pulmonary carcinomas showed that tumors were observed mostly in aged cats without sex predilection [ 147 ]. Persian cats may be affected more frequently [ 147 ]. Metastasis occurred in 80% of cases, mostly affecting lungs (intrapulmonary), pleura (intrathoracic), and regional lymph nodes [ 147 ]. Distant metastases were uncommon, and bone metastases were not observed [ 147 ]. The high rate of intrathoracic and extrathoracic metastases results in a poor prognosis and short survival time [ 148 ]. Cats have a unique phenomenon in which primary lung cancer can metastasize to soft tissues of the digits and pawpads and involve bones of the phalanges secondarily [ [149] , [150] ]. This clinical presentation is referred to as feline lung-digit syndrome (FLDS) [ 151 ]. FLDS is more common in elderly cats, with an average age at diagnosis of 12 years, although the condition has also been seen in younger cats (range 4–20 years) [ [152] , [153] ]. Metastatic tumors of the digits cause local signs such as lameness or paw pain, and not pulmonary disease associated with the primary neoplasm. Multiple paws and digits are commonly involved in FLDS, with the weight-bearing central digits most affected [ 147 ].

Non-metastatic tumor-bone interaction: oral squamous cell carcinoma

Feline oral squamous cell carcinoma (OSCC) serves as a unique and promising model for human head and neck squamous cell carcinoma (HNSCC). Oral cancers account for 10% of all cancers diagnosed in cats, and 75% of feline oral cancers are SCC [ 154 ]. Papillomavirus, tobacco smoke, and alcohol consumption are considered significant risk factors for HNSCC in humans [ 155 ]. Cats living in households with smokers are more likely to develop OSCC when compared to those in non-smoking households [ 156 ]. However, the relationship between papillomavirus and feline OSCC is not well established due to the low presence of feline papillomavirus in OSCC [ 157 ]. OSCC is particularly common in aged cats with no breed or sex predisposition [ 137 ]. Feline OSCC is extremely aggressive, as characterized by the destruction of oral tissues and bone invasion. Gingiva, sublingual location, and tongue were commonly affected sites [ 158 ]. Cats can develop sublingual SCC, similar to humans, which is an unusual location for oral SCC in other species [ 139 ]. Approximately 14–18% of feline OSCC spreads to local lymph nodes and about 12% to the lungs [ 139 ]. Adjacent bone invasion, lymph node metastasis, and frequent spontaneous recurrence after therapy in feline OSCC recapitulate the progressive behavior of human HNSCC [ 159 ]. A study evaluating 451 cases of feline OSCC showed that 37% of biopsies involved bone, and osteolysis was the predominant bone phenotype [ 160 ]. In addition, specimens with osteolysis had increased parathyroid hormone-related protein (PTHrP) expression and nuclear localization of the protein, compared to OSCC without osteolysis, which indicated the potential role of PTHrP in bone resorption and tumor invasion in cats with OSCC [ 160 ]. Both humans and cats with invasive HNSCC have a high morbidity and a low survival rate [ 158 ]. The prognosis of OSCC is grave for most cats since they are usually presented for veterinary care in the later stages of the disease. Here, there is most commonly bone invasion and the time to death or euthanasia from diagnosis is approximately 2 to 6 months [ 161 ].

Rodents

Prostate cancer

Mice do not naturally develop PCa. The National Toxicology Program conducted a two-year study on 612 mice and reported no cases of spontaneous PCa [ 162 ]. Genetically modified mice can have long latency periods, variable penetrance, and infrequently develop invasive adenocarcinomas or bone metastasis [ 163 ]. Rats also generally have a low prevalence of PCa, though some strains frequently develop PCa with ageing, including Lobund-Wistar, Copenhagen, and ACI rats [ 164 ]. The Lobund-Wistar rat model has a high circulating concentration of testosterone and displays hormone-sensitive growth, which permits the development of spontaneous tumors in the dorsolateral and anterior lobes of the prostate [ 165 ]. Copenhagen rats, a hormone insensitive model, have a 10% frequency of microscopic PCa and less than 1% frequency of grossly manifested PCa at 36 months of age [ 166 ]. Approximately 40% of aging ACI rats (33–40 months of age) develop spontaneous intraductal/intra-acinar PCa in the ventral lobe [ [166] , [167] ]. Although rats can develop a range of cancer phenotypes in the prostate, they are rarely used as spontaneous models due to the low frequency of tumorigenesis, variability in phenotypes, long latency periods, and the lack of overt bone metastases.

There are also important anatomic differences in the prostate glands between rodents and humans. Rat and mouse prostate glands have four distinct lobes—anterior, ventral, dorsal, and lateral [ 168 ]. The anterior lobe represents the coagulating gland. Humans have a single lobe with four anatomic zones: central, transitional, peripheral, and fibromuscular [ 169 ]. The peripheral zone comprises about 75% of the tissue in the prostate and is considered to be the origin of the majority of human PCa [ 170 ]. The mouse dorsolateral lobe has been described as the most similar to the human peripheral zone, but there is a lack of evidence that demonstrates a direct relationship between any one mouse lobe and the zones of the human prostate [ [171] , [172] ].

Mammary cancer

Mice and rats frequently develop mammary tumors in long-term rodent toxicologic studies. In mice, spontaneous mammary tumor development is linked to infection by an exogenous mouse mammary tumor virus (MMTV) or endogenous provirus [ 173 ]. Both BALB/c and C57BL/6 mice have a low prevalence of spontaneous mammary carcinoma, while C3H strains frequently develop mammary tumors due to exogenous MMTV infection [ 174 ]. BALB/c pups fostered onto C3H female mice (BALB/cfC3H) will subsequently develop mammary carcinomas with age [ 174 ]. The 4 T1 mouse mammary carcinoma cell line derived from BALB/cfC3H mice is highly bone metastatic [ 175 ]. In rats, mammary tumors are predominantly benign and naturally occur in several strains, such as August, Albany-Hooded, Copenhagen, Fisher, Lewis, Osborne-Mendel, Sprague-Dawley, Wistar, and Wistar/Furth [ 176 ]. Malignant tumors, such as adenocarcinomas, are relatively rare and their prevalence of metastasis is low. In addition, most mammary adenocarcinomas in rodents are hormone-independent due to the fact they lose estrogen responsiveness rapidly during the course of cancer progression [4] . There is a low frequency of metastasis of mammary carcinoma in rodents. Metastases occur in regional lymph nodes or lungs but very rarely to bone [4] . Therefore, the usefulness of rodents as a spontaneous model of mammary carcinoma bone metastasis has been limited.

Spontaneous bone metastasis in other animals

Reported literature on spontaneous bone metastases in other animal species is scarce and limited to isolated single case reports and/or small case studies.

Rabbit

The overall tumor prevalence in laboratory rabbits has been low, ranging between < 0.5% and 2.7%. [ [177] , [178] ]. However, studies of laboratory rabbits generally have surveyed younger populations. Neoplasia is relatively common in aged pet rabbits. The frequency of neoplasia during the necropsy of pet rabbits (n = 2970, 0–180 months) was 14% across sexes and ages and nearly 20% in females [ 177 ]. Female pet rabbits 6 years of age or older had a nearly 67% tumor prevalence [ 177 ]. Metastasis, primarily to the lungs, occasionally developed in pet rabbits with uterine adenocarcinoma and mammary carcinoma [ 177 ]. Bone metastasis was not reported in this retrospective study, indicating rabbits are not an appropriate model for spontaneous bone metastasis.

Equine

Bone metastases have been reported in horses with melanoma, squamous cell carcinoma, and renal cell carcinoma, which are all bone metastatic in humans. Melanocytic neoplasms account for 19% of all equine cutaneous neoplasms, compared to only 1–5% of all malignant cutaneous tumors in people [ [179] , [180] , [181] ]. Most equine cutaneous melanomas have a benign behavior, but histologically benign dermal melanomas may eventually metastasize and thus should be considered potentially malignant [ 179 ]. Gray horses, which have progressive depigmentation of their fur with age, are predisposed to melanocytic tumors that can develop in the skin or internal organs [ [179] , [182] ]. Approximately 80% of gray horses over the age of 15 develop melanocytic tumors, most of which are benign [ 179 ]. A study of horses with metastatic melanomas found that 6/14 (42.8%) horses developed bone metastases [ 183 ]. The vertebrae, hindlimb, maxilla, and ribs were affected sites. Phenotypes of the bone lesions were not reported, and these bone metastases were not considered as the cause of death in these cases [ 183 ]. The involvement of bones has also been described in horses with squamous cell carcinoma and renal cell carcinoma [ [22] , [23] , [184] , [185] ]. Appendicular bones were the most affected sites, and osteolytic lesions with periosteal proliferation predominated.

Ferret

Ferrets have a high prevalence of neoplasia, predominantly affecting the endocrine and hemolymphatic systems [ [24] , [186] , [187] , [188] ]. However, common malignant solid tumors in humans and some domestic animals are rare or not reported in ferrets [ [187] , [188] ]. Metastasis of solid tumors in ferrets is uncommonly encountered but may occur with cutaneous, gastrointestinal, or renal carcinomas [ 188 ]. Lymphoma can involve bones, resulting in osteolysis, but bone metastasis of solid tumors has not otherwise been reported in ferrets [ 189 ]. Ferrets have a relatively high prevalence of chordomas, a generally non-metastatic but locally aggressive neoplasm of the notochord [ 188 ]. Chordomas often affect the axial skeleton and, while solitary, could produce clinical signs resembling bone metastasis [ 190 ].

Non-human primates

Among non-human primates, macaques are the most used long-lived primates in biomedical research. Rhesus macaques greater than 20 years of age have a high risk of developing neoplasia, which results in more than half of the reported deaths in rhesus macaques older than 26 years [ 191 ]. While cancer can be found commonly in aging non-human primates, the overall frequency of cancer is low in the population, and bone metastasis is rarely observed.

Discussion

The review described the natural history of spontaneous bone metastasis across studied non-human animal species for reference by veterinary-clinician and biomedical researchers. Spontaneous or natural disease in non-human animal populations is a potentially promising, though often overlooked, bridge between experimental systems and human clinical trials. Spontaneous cancers in animals encompass a full natural history from initiation to metastasis, interactions with a diverse immune response, and induction of heterogeneous microenvironments, all within a shorter timeline compared to humans. Malignant tumors in animals can share similar disease courses, histologic features and subtypes, and genomic mutation or other molecular similarities with humans [ [28] , [31] , [192] , [193] , [194] ]. Companion animals (e.g. dogs and cats) in particular share our immediate environment and are an increasing focus of intense veterinary clinical and comparative research [ 195 ].

Even with recent advances in veterinary clinical medicine and biomedical research, publications on spontaneous bone metastasis are sparse, with no comparative studies. This is surprising given that bone metastasis in companion animals is widely recognized in veterinary centers, carries a poor prognosis, and shares comparative aspects in tumor types, bone phenotypes, affected skeletal locations, and clinically evident skeletal-related events. Lack of veterinary specialization coupled with late-stage occurrence, ineffective anti-cancer therapies, and concerns with quality of life have likely all historically contributed to slow progress in veterinary bone metastasis research. However, even with older figures, the prevalence of bone metastasis in dogs with mammary, urogenital, pulmonary, and primary bone tumors is 10–40%. Some of these tumor types are also common. Additionally, veterinary medicine is advancing, with 10 new or planned colleges in the last four years, increased specialization among graduates, and, importantly, greater access to and demand for advanced medicine. As newer therapies for primary tumors prolong overall survival in companion animals, bone metastasis and the expectation for mitigation may increase [ [35] , [69] ].

Companion animals are pre-existing cancer populations that contribute clinicopathologically relevant disease characteristics and translational opportunities. The Comparative Oncology Program established by NCI has provided the infrastructure and resources needed to incorporate veterinary oncology research into the process of developing new therapies for human cancer [ 196 ]. Studies conducted on dogs with cancer have provided evidence of the clinical efficacy, dosage tolerability, and assessment of toxicity of anti-cancer drugs. For instance, Phase I/II veterinary trials not only demonstrated anti-tumor activity but also gave valuable insights into toxicity profile and dosing schedule prior to human clinical trials [ [197] , [198] , [199] ]. The synergic effect of PAC-1 and doxorubicin in the induction of cancer cell death was first evaluated in dogs with naturally occurring metastatic osteosarcoma or lymphoma [ 200 ], leading to a human trial ( NCT02355535 ) for treating advanced malignancies, including breast cancer, lymphoma, and melanoma. [ [201] , [202] ].

Companion animal translational research has also contributed to immune cell-cancer interactions that are increasingly recognized in the pathogenesis of bone metastasis [ 203 ]. Companion animals are exposed to prophylactic immunizations, viral and bacterial infections, and a similar environment as humans prior to the development of cancer. These immunological events modify the immune repertoire of dogs and cats and render them more immunologically similar to human [ 204 ]. The immune system additionally has a long period to recognize the tumor and develop the complex interplay with the immune system before diagnosis. The long-term exposure to tumor microenvironment educates the host immune system in a way that cannot be mimicked in implanted or induced tumor models. For example, the increased number of activated regulatory T lymphocytes (Treg) has been found in many human and canine cancer patients and is associated with a suppressed immune response, poor prognosis, and bone metastases [ 205 ]. Immunotherapies have been evaluated in canine clinical trials of lung-metastatic osteosarcoma to inform researchers studying the human pediatric disease [ [206] , [207] ]. In addition, the effectiveness of L-MP-PE, an immunomodulatory drug, in dogs with osteosarcoma resulted in its evaluation in human clinical trials [ 208 ].

The practical integration of companion animal spontaneous bone metastasis into the larger field of comparative and translational research requires some considerations and cross-disciplinary collaboration. Some of the discussion is beyond the scope of this review but has been recently described elsewhere [ 195 ]. To start, preclinical, experimental translational research would benefit from the incorporation of non-rodent (e.g. canine) cells, tissues, and in silico data, all now available, to determine target availability and screen genomic mutations or compounds. Cost, species prevalence of disease, and species differences in anatomy/physiology are all study considerations for later stage translational research. The available literature suggests bone metastasis is common in dogs for some solid tumors (e.g. mammary), though it is rare in other studied non-human animal species. Dogs are most likely the best spontaneous species for studying mammary cancer metastasis, AR-negative PCa osteoblastic bone metastases, and osteosarcoma, while cats would serve as an optimal model for the investigation of osteolytic bone metastases/invasion induced by OSCC. However, veterinary clinical trial recruitment is still challenging and will require multi-institutional collaboration and outreach to local general veterinary practitioners desperate for new therapies. Low recruitment can still produce valuable safety and pharmacokinetic data through pilot (proof-of-concept) studies, as demonstrated by canine primary and lung-metastatic osteosarcoma [ [198] , [206] ]. Further, while trial samples sizes may be low, the value of translational research is faster recruit of animal patients and faster determination of upscaled safety and target availability before moving it to humans.

Conclusion

Animals with naturally occurring bone metastases serve as invaluable natural, pre-existing cancer models, mimicking the spontaneous progression and subsequent lesions of bone metastases seen in humans. Dogs in particular have a relatively high rate of bone metastasis and are a current focus US federally supported translational research. The infrastructure, knowledge, and need already exist to successfully recruit companion animals similarly suffering from bone metastasis and support translational research. The integration of animals with spontaneous bone metastases between studies on experimental models and human clinical trials will provide unique insight into the mechanism of metastases and the development of potential therapeutic opportunities for both human and veterinary patients.

CRediT authorship contribution statement

Shiyu Yuan: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. Nathan K. Hoggard: Writing – review & editing, Writing – original draft, Methodology, Data curation, Conceptualization. Evan T. Keller: Writing – review & editing, Supervision. Brad M. Matz: Writing – review & editing, Visualization, Resources. Shi Wei: Writing – review & editing, Visualization, Resources. Timothy M. Fan: Writing – review & editing, Visualization, Resources. Blake E. Hildreth: Writing – review & editing, Visualization, Supervision, Resources, Conceptualization. Thomas J. Rosol: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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