Submitted by: Patricia Shea, DVM
J Vet Intern Med 2022;36:1398-1408
Environmental risk factors for the development of oral squamous cell carcinoma in cats.
Zaccone R, Renzi A, et al.
Squamous cell carcinoma, the most common oral tumor in cats, is also the deadliest and usually the least treatable, due to the rapid growth and pronounced local invasiveness of this neoplasm. In addition, these tumors are not often diagnosed until in an advanced stage. The last study to identify environmental risk factors for the development of feline oral squamous cell carcinomas is now over two decades old. Environmental tobacco smoke, flea collars, canned cat food, and canned tuna were the significant environmental and lifestyle risk factors for oral squamous cell carcinoma (OSCC) in cats in this older paper.
In this prospective, observational, epidemiological case-control study, the authors compared 100 cats with confirmed OSCC to an age-matched control sample of 500 client-owned cats, as well as to a group of 70 cats with chronic gingivostomatitis (CGS), and another group of 63 cats with periodontal disease (PD). Given that there is a demonstrated association, with increasing evidence, between oral inflammation and neoplasia in humans, there is concern that a similar link is also likely in felines, especially because an altered DNA methylation profile of tumor-related genes has been discovered in cats with stomatitis. Current literature suggests that a majority of cats (50-90%) older than four years of age have some type of oral inflammatory disease: gingivitis, PD, and/or tooth resorption.
Cats diagnosed with OSCC via histopathology or cytopathology between 2018-2020 were included in the study after the owner completed an anonymous online questionnaire. This questionnaire encompassed demographic information, as well as an inquiry regarding the cat’s lifestyle, diet, and living environment. The patients had to have lived in their current household for at least three years before their OSCC diagnosis to be included in the study so that significant historical information would be available for evaluation. The OSCC group comprised 90 mixed breed cats and 10 purebred cats (five Chartreux, two Siamese, and one each of Persian, Maine Coon, and Korat). The median age of these animals was 13 years (range, 5-21 years); 46 were neutered males and 54 were spayed females.
The control group was recruited by sending the same questionnaire to random cat owners via social networks. Potential control group participants were excluded from the study if they had ever had oral tumors. There were seven (1%) intact males, 215 (43%) neutered males, eight (1%) intact females, and 270 (54%) spayed females in the control group; 88% (n = 440) were mixed breed cats, and 60 (12%) purebred cats. As these animals were age-matched to the OSCC group, the median age of the controls was also 13 years.
Cats with PD or CGS were also recruited in 2018-2020 from patient populations at a university veterinary hospital and two private veterinary clinics. Owners of these cats also prospectively completed the same questionnaire. The median age in the PD group was nine years (range, 2-18 years). Almost all of these cats were either spayed females (n = 24; 38%) or neutered males (n = 36; 57%); 84% (n = 53) were mixed breed, and 16% (n = 10) were purebred. In the CGS group, there were 63 (90%) mixed breed cats and seven (10%) purebred cats; only two were intact (males), and the rest were 34 spayed females (49%) and 34 neutered males (49%).
This prospective study was preceded by a retrospective analysis of almost 600 cases of feline OSCC accumulated between 2000-2021 by the pathology service of a university veterinary teaching hospital. In this study, the large sample size allowed for the demographic characterization of cats with OSCC before the completion of the current prospective study. In the retrospective study group, the median age of the patients was 13 years (range, 1-21 years); 90% (n = 526) were mixed bred and 10% (n = 61) were purebred. 44% were males (n = 266) and 56% (n = 328) were females. A history of oral inflammation was evident in 24% (n =143) of the patients; 44 (31% of the 143 with oral inflammation history) had recurrent gingivostomatitis, periodontitis, multiple dental extractions, or eosinophilic granuloma. Information regarding feline leukemia (FeLV) and feline immunodeficiency virus (FIV) status were available in 17% of the 594 retrospective OSCC cases; 13% were FIV-positive and 3% were FeLV-negative.
Univariable logistic regression analysis of the case cats in the prospective study, compared with the controls, demonstrated that covariates significantly associated with the risk of developing OSCC included a rural living environment, outdoor access, wet diet, consumption of cat food brands with high quantities of chemical additives (coloring agents, flavor enhancers, and preservatives), consumption of low-cost cat foods (those with no fixed ingredient formulation and sold by discount and mass-market retailers), and FIV positive status. The OSCC group and the CGS group shared outdoor access as a significant risk factor for their diseases, while the PD and OSCC groups had wet food as 50% or more of their diet and diets with high amounts of chemical additives as a risk factor for their diseases.
When the data were subjected to multivariable analysis, significant risk factors for OSCC were rural living environment, outdoor access, indoor smoking by owners, and consumption of commercial cat foods containing high amounts of chemical additives. Concerning CGS, the risk factors of significance were outdoor access, cohabitation with other cats, endectocide drugs, and FIV positive status. For PD, the identified risk factors were male sex, cohabitation with other cats, a diet composed of 50% or more wet food, and consumption of cat foods with high amounts of chemical additives.
Correlations between behavior and hormone concentrations or gut microbiome imply that domestic cats (Felis silvestris catus) living in a group are not like ‘groupmates.’
Koyasu H, Takahashi H, et al.
Most wild felids are solitary and exclusively territorial. Yet domestic cats can and do live in high-density groups, and interact with each other within these groups. It is possible that domestication and its attendant opportunities for novel food resources such as rodents infesting granaries associated with human settlements have selected feline temperaments that tolerate high-density living situations and communal feeding.
These investigators wondered if the transition to domestication and group living that the formerly solitary and exclusively territorial animal, Felis silvestris catus, underwent, caused these creatures to develop group formation strategies similar to those of typical group-living species. Are domestic cats true “groupmates” like other animal species whose natural, historical inclination is to live in groups? Or do they barely tolerate communal living arrangements, or could they conflict with each other while living in a group?
There are biological foundations underlying the social behavior of animals living in groups. Specifically, endocrine activity, as measured by glucocorticoid, testosterone, and oxytocin levels, and the gut microbiome, are instrumental in regulating behaviors that promote tolerance of and success in high-density living. Typically, high cortisol and testosterone concentrations promote less social tolerance and more aggression-related behaviors in individual animals. High oxytocin levels in an animal are associated with a preponderance of affiliative behaviors and decreased aggression. The gut microbiome composition and hormone levels in an individual’s body are interrelated, and animals who have frequent contact with each other have similar gut microbiomes.
These investigators sought to learn whether the foregoing generalizations regarding the influence of endocrine hormones and the gut microbiome on the ability to tolerate group living apply to the domestic cat. This study, the first to report the role of oxytocin on conspecific social behaviors in a historically solitary mammal, the cat, utilized 15 shelter cats, 10 neutered males, and five spayed females, with a mean age of 4.2 + 2.3 years. The cats were divided into three groups of five cats each, and each group was housed successively in the same 4 m x 7.5 m room for two weeks. The room contained more than five beds, so each cat could choose their own resting spot, two food bowls, two water bowls, and five litter trays. Access to food and water was available at all times. All cats were fed the same food, a complete and balanced commercially available kibble. The cats were found to be both more active and more interactive at night, so infrared lights were left on between 21:00 h at night to 7:00 h the following morning, and these were the hours during which the behavior of the cats was observed and analyzed.
Urine samples were collected from the cats immediately after urination using a two-tiered litter box. Cortisol, testosterone, and oxytocin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and standardized to urine creatinine. Fecal samples were used to evaluate the gut microbiome, and these samples were collected only when the cats excreting them were observed. Only eight of the cats provided fecal samples. A hierarchical cluster analysis was performed on the bacterial populations in the fecal samples based on the percentage of similar microbes in the cats at the genus level.
No significant effect of sex on any of the hormone levels was identified. In the case of cortisol, negative correlations were observed between cortisol levels and contact among cats as well as with food-sharing behavior. Active following of another cat, active playing, passive playing, sharing food, and passive sniffing behaviors were all significantly negatively correlated with cortisol concentration. Concerning testosterone, there was a significant positive correlation between testosterone concentration and active escape behavior. No correlation was found between testosterone and aggressive behavior in the subjects.
Oxytocin levels, similar to cortisone concentration, were surprisingly negatively correlated to contact among cats and food sharing. There were significant negative correlations observed between oxytocin concentration and active allogrooming, passive following, passive playing, food sharing, and both active and passive sniffing. Compared with other group-living animals, domestic cats with high oxytocin levels paradoxically demonstrated less affiliative behavior with other cats. It appears that cats can spend time together in the same space, but may not form a truly closely knit group, as each cat may continue to view other feline group members as outsiders. The only correlation between levels of the three different hormones was a significant positive correlation between cortisol and testosterone concentrations.
There is a complex interaction between food resource niches, the gut microbiome, and endocrine activity. The gastrointestinal microbiome not only interacts with processes in the digestive tract, but also with the brain, and this interaction with and influence on the brain (the brain-gut axis) occurs in part through endocrine pathways, including those involving sex steroids, glucocorticoids, and neuropeptides. Gut microbes can produce these hormones directly or indirectly; the gastrointestinal microbiome significantly influences the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, and can also modulate oxytocin secretion from the hypothalamus. Members of a group are likely to experience microbial transmission among themselves via social interactions or shared environments, which promotes the development of similar microbiomes in groupmates.
The greater the similarity of the gut microbiome between two of the study cats, the more likely they were to share a bed, enter a bed, or engage in sniffing. However, no correlation was found between allogrooming and gut microbiome similarity in the study cats.
The limitations of this study, although pioneering in its findings around the role of oxytocin levels in domestic feline groups, are significant and recognized by the authors. Cats enrolled in the study were only studied in their groups for two weeks; longer-term studies of cats experiencing group living may yield different results regarding the correlation between hormone levels, the composition of the gastrointestinal microbiome, and behavior among individuals in a group. Future experiments with cats raised from their juvenile period in the same group, same-sex groups, and family groups are likely to expand the knowledge obtained from this pilot study. Observation of domestic cat groups in environments that provide significantly more enrichment and multiple resources than those employed in the present study may also reveal more about the hormonal, microbiological, and behavioral phenomena that have evolved to allow a historically solitary and exclusively territorial species to cohabit with conspecifics.