Effect of Dietary Phosphorus on Incidence of Lung Cancer Metastasis to Bone Pubblico
Alappan, Uma D. (Spring 2022)
Abstract
Lung cancer is one of the most commonly diagnosed cancers in the US. In lung cancer patients, incidence of bone metastasis is ~40%. Malignant tumor cells can successfully colonize, grow, and flourish in secondary sites like bone by hijacking bone remodeling processes to create a feedforward loop (“vicious cycle”), promoting tumor growth. Phosphorus (Pi) – a vital nutrient for homeostatic processes and cell growth – can alter energy metabolism gene expression and create low-grade inflammation in bone microenvironments to support cancer proliferation/outgrowth.
Our study aims to further define the role of Pi in lung cancer progression & bone metastasis and identify robust gene marker(s) which can be used to identify occurrence of lung tumor bone metastasis. We hypothesize that 1) a high Pi-diet will increase lung cancer metastasis to bone, and 2) cells that metastasize to bone can be detected in bone marrow by lung “signature” genes using qRT-PCR to measure gene expression. Using a novel KLLLenti model, 12–15-week-old mice were enrolled in a high or low Pi diet (HPD, LPD) 2-weeks post-infection with tumor-inducing lentiviral-Cre (1x10ˆ6 i.u). Mice were fed diets similar in protein/Kcals/fat. At 30-weeks, mice were sacrificed, and RNA & qRT-PCR, lung histology (H&E stains), and bone metastasis analysis (bone X-rays) were performed.
The results demonstrated that HPD significantly increased bone metastasis. HPD significantly increased tumor growth in females. Additionally, novel gene markers of lung cells were identified in bone marrow with high specificity to detect bone metastasis. TTF1 and PTHrP expression in lung tissue correlated with both Pi-diet and tumor growth. Our identified genes could be used as powerful lung cell markers to perform further analyses (ex – single-cell analyses) to determine additional genes/signaling associated with lung cancer metastasis to bone. Other labs may benefit from using our novel KLLlenti transgenic model to perform additional studies assessing direct relationships between lung adenocarcinoma and metastasis.
Table of Contents
Introduction: ………………………………………………..………………….……..9
Fig. 1: Pi Homeostasis ……………………………………………………..10
Project Aims …………………………………………………………….…….……..12
Hypotheses …………………………………………………………………..………12
Fig. 2: Bone metastases in KrasG12DLkb1fl/fl mice after ~20 wks………13
Fig. 3: Histological sections of tibia (cortical) with H&E stain………..….14
Experimental Approaches ……………………………………………………….…15
Table 1: Primer sequences for genes analyzed with qRT-PCR………..16
Results ………………………………………………………………………….……18
Fig. 4: Study Design……………………………….………………………..18
Fig. 5: Kaplan Meier’s Survival Curves for Female and Male Mice…….18
Fig. 6: Lung H&E; Box Plot of Lung Tumor Growth vs. Diet..…………..19
Table 2: Lung Tissue Genes v Bone Mets / Pi/ Tumor Growth ………...20
Fig. 7: PTHrP Expression in Lung Tissue………..…………..……………20
Fig 8: Incidence of Bone Mets by Diet & Sex……………………………..22
Fig 9: SCGB1A1 and SFTPC Cut-Off Values……………………..….….24
Table 3: Bone Marrow Genes v Bone Mets / Pi Diet……………………..25
Fig 10: SFTPC Expression in Bone Marrow……………..……………….26
Fig 11: Incidence of Bone Mets by Diet & Sex: SCGB1A1 & SFTPC….26
Discussion …………………………………………………………………….……..27
Fig 12: Pi-Related Pathologies……………………………….…………....29
Sources ……………………………………………………………..………………..31
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