In this issue, we will meet you with a lung cancer model - KS mice, let Xiao Sai take you to understand lung cancer first. Lung cancer is the most common cancer worldwide, with more than 2.2 million new cases of lung cancer worldwide in 2020. According to data released by the National Cancer Center, as early as 2015, lung cancer ranked first in terms of the number of cases and deaths caused by lung cancer in China [1]. The high incidence and mortality of lung cancer has placed a huge burden on the world's public health, and more clinical and preclinical studies are urgently needed.
Mortality rates from the 10 most common cancers in China from 1990 to 2015.
Genetic mutations and the development of lung cancer
Lung cancer is divided into two histological subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers and small cell lung cancer (SCLC) accounting for 15%. Non-small cell lung cancer (NSCLC) can be further divided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), and large cell lung cancer (LCC). KRAS is the most common pathogenic gene in NSCLC, which plays a tumor suppressor role as an information center for cell growth signals in normal cells, and mutations cause KRAS to be in a state of continuous activation, resulting in uncontrolled cell proliferation and development into adenocarcinoma in NSCLC. KRAS G12D is a common mutation in lung cancer, and the construction of a variety of lung cancer models is also based on KRAS G12D overexpressing mice.
Common causative genes in non-small cell lung cancer (NSCLC) [2].
Recently, Ferone et al. summarized the characteristics of different mouse models of lung cancerIt was found that characteristics such as tumor heterogeneity, erosion, and resistance to response to ** in a mouse lung cancer model were determined by both the origin cell and the genetic lesion. For example, studies have shown that alveolar cells carrying KRAS or EGFR pathogenic mutations are the primary origin of LUAD, while the proliferation of club cells carrying mutations is more likely to exhibit a papillary tumor phenotype.
SFTPC is a marker gene for alveolar cells, and Cyagen will conditionally overexpress the KRAS G12D mutationLSL-K-RAS G12D mice (Product No. C001064).withSFTPC-Mercremer mice (Product No. C001501).Mating yielded offspring and was induced by tamoxifen to obtain cells driven by the KRAS G12D mutation and originating from SFTPC-positive alveolar cellsKS Lung Cancer Mouse Model (Product No.: C001514).
KS mice after 6 weeks of tamoxifen treatmentSignificant tumor tissue infiltration occurs in the lungs
Low-dose spiral CT is a lung cancer screening technique recommended by the Chinese Lung Cancer Screening Standards [6], and Cyagen performed lung CT scans on early KS mouse models to determine the occurrence of tumors. The results showed that after 6 weeks of tamoxifen treatment, significant tumor tissue infiltration appeared in the lungs of mice.
Significant tumor tissue infiltration appeared in the lungs of 4-week-old KS mice after 6 weeks of tamoxifen treatment (light-shaded part in the figure).
The results of hematoxylin-eosin (H&E) staining of KS mice at the same period showed that the lung tissue tumor was infiltrated, and obvious lesions appeared, and the late phenotype was reached at 12 weeks.
H&E staining showed significant infiltration of lung tissue tumors in 4-week-old KS mice after 6 weeks of tamoxifen treatment, and the lesions further aggravated after 12 weeks.
KS mice have abnormal growth and development
Growth curve and survival curve data show that:The body weight of KS mice treated with tamoxifen was significantly lower than that of wild-type mice, and this trend was present in both females and males. In addition, the survival rate of KS mice began to decrease at 9 weeks after tamoxifen induction, and all died after 13 weeks of induction, which is consistent with the survival time reported in the literature.
Growth curves and survival curves of KS mice.
KS mice had abnormalities in the lungs and spleen
The lungs of KS mice at different stages after induction were observed, and the data showed that compared with wild-type miceAt the 6th week after the induction was completed, the lungs of KS mice showed tumor cell invasion, and their lungs showed a dense and enlarged structure. After the induction was completed, the spleen of KS mice showed abnormal hyperplasia.
KS mice have dense and enlarged lung structures and abnormally proliferative spleens.
Lesions in other tissues
The spleen, kidney, liver and pancreatic tissues of KS mice 12 weeks after the completion of induction were detected by H&E stainingThe results showed that there were no abnormalities in the kidneys, liver, and pancreas compared to the control group, but there was abnormal white pulp hyperplasia in the spleen.
H&E staining of kidney, liver, spleen, and pancreatic tissues of KS mice 12 weeks after induction completion.
Summary
KS mice begin to lose body weight 6 weeks after tamoxifen induction, develop symptoms of dyspnea with age, and all die at 13 weeks after induction. Specific to the pathological phenotype, KS mice began to have obvious tumor cell infiltration in the lungs 6 weeks after induction, and the lungs were distended and deformed, showing a dense structure and ruddy appearance of the tissue structure, and reached an advanced stage 12 weeks after induction. Therefore,KS mice provide a long experimental window for mechanism research and drug development while ensuring the efficient and rapid development of tumors, and also provide a more suitable preclinical tool for the evaluation of KRAS-targeting G12D**.
In addition to the KS lung cancer mouse model, Cyagen also offers a range of inclusionsMultiple spontaneous, induced, or CDX tumor models including liver, pancreatic, breast, and gastrointestinal cancers。At the same time, it can also be customized or co-developed according to the needs of researchers.