Chronic Stress Enhances Glycolysis and Promotes Tumorigenesis

doi:10.21203/rs.3.rs-3957233/v1

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Chronic Stress Enhances Glycolysis and Promotes Tumorigenesis

https://doi.org/10.21203/rs.3.rs-3957233/v1

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Depression is a well-known risk factor for tumors, but the mechanisms other than inflammation are unclear. Aerobic glycolysis is considered to be a critical element in the reprogramming of energy metabolism in malignant tumors, and impaired glycolysis has been reported in the brains of chronic stress mice. Therefore, this study aimed to explore the role of glycolysis in which depression promotes tumorigenesis. We examined the impacts of chronic unpredictable mild stress (CUMS) on the growth and metastasis of breast cancer (BC) and lung cancer (LC). The findings showed that both CUMS and tumors induced depressive-like behavior, neuronal damage, and impaired synaptic plasticity in mice, while CUMS also enhanced tumor development and metastasis in both BC and LC. In the brain, both CUMS and tumor alone and in combination significantly reduced glycolytic products and enzyme levels. However, CUMS significantly enhanced the levels of aerobic glycolytic products and enzymes in tumor tissue. Collectively, our results provide insights into that down-regulated glycolysis in the brain, leading to depression-like behavior, and how depression, in turn, enhanced glycolysis and promoted tumorigenesis.

CUMS

metastasis

tumorigenesis

glycolysis

orthotopic

Both CUMS and tumor-induced depressive-like behavior, neuronal damage, and impaired synaptic plasticity in mice,
CUMS can enhance tumor development and metastasis in both BC and LC.
In the brain, both CUMS and tumor alone and in combination significantly reduced glycolytic products and enzyme levels.
In tumor tissue, CUMS significantly enhanced the levels of aerobic glycolytic products and enzymes.
This study validated the potential mechanism of glycolysis in depression-promoted tumorigenesis and development.

Patients diagnosed with cancer often concurrently suffer from depression [1, 2], the negative emotions induced by this psychological condition can potentially stimulate tumor growth and metastasis of tumors [3–5]. Past studies have unequivocally shown that chronic stress significantly affects every stage of cancer development in patients, ranging from carcinogenesis to angiogenesis stimulation and metastatic dissemination [6]. Chronic stress-induced inadequate coping, negative emotional responses, or a diminished quality of life are associated with an increased risk of cancer incidence [7]. Annually, approximately one million new cancer cases are diagnosed in young individuals aged 20–39 years, primarily attributed to chronic stress [8]. A poor prognosis and elevated mortality are observed among cancer patients concurrently suffering from comorbid depression [6]. Cancer patients exhibit a depression morbidity of approximately 12.5%, which is up to fourfold higher than that of the general population [9]. Chronic stress has been demonstrated in studies to raise plasma catecholamine levels, including epinephrine and noradrenaline, and accelerate the aggressive development of BC, ovarian carcinoma, and gastric cancer [10, 11]. However, the research concerning the relationship between chronic stress and cancer remains limited.

Otto Warburg and colleagues ascertained in the 1920s that tumor cells, under aerobic conditions, exhibit a preference for generating energy via a process termed aerobic glycolysis. This is manifested by excessive glucose absorption and lactate accumulation, a phenomenon known as the Warburg effect [12, 13]. To fulfill uncontrolled biosynthesis and energy demands, cancer cells frequently tend to perform aerobic glycolysis [13]. In numerous cancer patients, clinical investigations utilizing the imaging technique of positron emission tomography (PET) with the glucose analog tracer 18fludeoxyglucose (FDG)^6–8 have unambiguously demonstrated a substantial elevation in glucose absorption in the majority of metastatic and primary human cancer patients [14]. Tumor cells facilitate the formation of new blood vessels through the secretion of VEGF, induced by lactate, which supplies sufficient oxygen and nutrients for proliferation [15]. Persistent chronic stress triggers a decrease in lactate levels and leads to depression. Intriguingly, stress-induced epinephrine enhances breast cancer stem-like characteristics through LDHA (lactate dehydrogenase A) - dependent metabolic reprogramming [11]. Lactate performs antidepressant functions by maintaining normal neuron function, and modulating levels and activity of histone deacetylases in the hippocampal region[16]. Meanwhile, LDHA regulats neuronal excitability to inhibit depressive-like behavior through lactate homeostasis [17]. However, the research on lactate levels in depression and cancer models has been a gap in the literature. To address this, we developed an animal model of breast cancer-related depression (BCRD) by in situ injection of BC cells into CUMS mice and a model of lung cancer-related depression (LCRD) by injecting LC cells into the tail veins of CUMS mice. Behavioral assessments and synapse plasticity detection were used for depression evaluation, while tumor volume and H&E staining were performed to examine tumorigenesis. Metabolites and key functional enzymes were detected to unveal the role of glycolysis in depression-promoted tumor glycolysis.

The findings of this research highlight the potential role of chronic stress in exacerbating tumorigenesis and metastasis through the stimulation of glycolysis.

Cell culture

Luciferase gene-tagged Lewis murine lung cancer cell (LLC-Luc) and luciferase gene-tagged 4T1 murine breast cancer cell (4T1-Luc) were purchased from the Chinese Academy of Sciences Cell Bank (Shanghai, China). LLC-Luc cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Gibco-BRL, Grand Island, NY, USA); the 4T1-Luc cells were cultured in RPMI-1640 medium (Gibco-BRL, Grand Island, NY, USA); all mediums were supplemented with 10% fetal bovine serum and cultured at 37°C in a humidified incubator containing 5% CO₂.

Animals

Six–week–old female BALB / c mice and male C57BL / 6 mice were purchased from the Guangdong Medical Laboratory Animal Center (Guangdong, China), and housed in special-pathogen-free ventilation facilities. 12 h / 12 h light/dark cycle was carried out, with ambient temperatures of 20–26 ^o C and relative humidity of 40–70%, 5 mice per cage, and eating and drinking freely. The Ethics Committee of Guangzhou University of Chinese Medicine has authorized a laboratory animal protocol.

Chronic unpredictable mild stress experiment

Chronic unpredictable mild stress (CUMS) might mimic the onset of depression produced by various pressures in human daily life [5, 18]. Mice were exposed to CUMS for 8 weeks, which included day-night reversal (24 h), cold-water swimming (10°C ± 1°C, 3 min), crowd-feeding (24 h), water and food deprivation (24 h), an empty water bottle (24 h), a 45 ° cage tilt (24 h), a tail clamp (1 cm from the tail end, 60 s), a self-made plastic seal tube (3 h), and a wet pad (24 h). 2 or 3 stimulation modalities were chosen randomly each day to ensure no repetition within 2 days.

Establishment of tumor orthotopic transplantation

5 × 10⁵ 4T1-Luc cells were injected into the right second mammary fat pad of BALB/c mice for orthotopic transplantation of BC. CUMS mice were inoculated with 4T1-Luc cells to develop BCRD. The tumor size of BC was measured with an vernier caliper every two days. It was calculated as follows: tumor volume (mm³) = [length × width²] / 2.

1 × 10⁶ LLC - Luc cells were injected into the tail vein of C57BL/6 mice for orthotopic transplantation of LC, and CUMS mice adopted LLC-Luc cells to develop LCRD. The tumor size was evaluated every week using IVIS (PerkinElmer, Boston, United States) with 150 mg/kg of D-luciferin potassium salt (PerkinElmer, Boston, United States) given intraperitoneally.

Behavior assessments

The sucrose preference test (SPT) is done for anhedonia assessment. Mice were fed in solitary cages preferentially. Two bottles containing 1% sucrose solution were placed at each side of the cages for 24 hours as an adaption phase. The next day, one bottle was replaced with water and left for another 24 hours, and two bottles of solution were changed the position at 12 hours to avoid the error caused by location preference. Then, mice were formally tested after 24 hours of freely eating without water, one bottle of water and one bottle of 1% sucrose solution were placed on each side of the cage and switched at 12 hours. 24 hours later, weigh each bottle and calculate sucrose preference (%) = sucrose consumption / (water consumption + sucrose consumption) × 100% [19].

An open field test (OFT) was also performed. BALB/c mice were set up in the center of the blackboard, while C57BL/6 mice were on a whiteboard and 10 minutes for each mouse. The open-field arena is 50 × 50 × 40 cm (length × width × height). The mice’s activity was filmed using a digital camera, and the total distance, center distance, and center time were calculated using software.

The tail suspension test (TST) was done as follows, mice were suspended 30 cm above the ground with wide tape on the tail-suspension device for 6 minutes and recorded with a digital camera recorded the mice's activity. The first 2 minutes are considered familiarity time and only the last 4 minutes are counted.

Mice were placed in cylindrical containers filled with room-temperature water at a depth of 30 cm for forced swim test (FST). Each mouse swam for 6 minutes and was videotaped, and then blow-dried the mice hair and put them back. The first 2 minutes are considered familiarity time and only the last 4 minutes are counted.

The Y-Maze test was considered evaluable for working memory and exploratory behavior in mice. Mice were placed on either of three identical arms (arm length: 35 cm, arm width: 5 cm, wall height: 10 cm) and were allowed to explore freely for 8 minutes. The percentage of spontaneous alternation was calculated as alternation (%) = (number of correct alternations) / (number of total arm entries-2) x 100% [20].

1.5.5 Elevated plus-maze test (EPM) was used to investigate the anxiety-related behavior in rodents The maze consists of four arms: a pair of open arms and a pair of closed arms (35 cm long, 5 cm wide, and 10 cm high), which were connected by a central platform. The maze rises 50 cm above the ground. Gently place the mouse in the central area facing the open arm and track the mouse's movements within the elevated cross-maze instrument. Record the number of entries and the time spent in each arm [21].

Western Blot

Tissue protein was extracted with ice RIPA and was detected with a BCA kit following the guidelines. The protein samples were split using SDS-PAGE, moved to a PVDF membrane, and then treated with primary antibodies such as HKII (hexokinase II), PFKP (phosphofructokinase platelet type), PKM2 (pyruvate kinase isozyme type M2), PDH (pyruvate dehydrogenase), and LDHA overnight at 4°C. After incubation with enzyme-linked secondary antibody, the target protein level was detected with a super-ECL detection reagent.

Glycolytic metabolites measurement

The contents of the ATP colorimetric kit (Cat.#A095-1-1), pyruvate test kit (Cat.#A081-1-1), and lactic acid assay kit (Cat.#A019-2) were obtained from Nanjing Jiancheng, Nanjing, China and followed the manufacturer's instructions.

Hematoxylin and eosin staining (H&E), Nissl staining

After being fixed with 4% paraformaldehyde for 24 hours, the tissue samples were paraffin-embedded and sliced into 4 µm. The tissue sections were deparaffinized with xylene and graded alcohol. According to the standard protocol of H&E staining eosin dye for 3 minutes hematoxylin dye for 10 minutes. Standard Nissl's staining method was performed.

Immunohistochemistry

Tissue slices were deparaffinized, and antigen recovery was performed in citrate buffer (pH = 6). Then slices were incubated with the specific antibody HKII (AB227198) in the wet box at 4°C overnight. The DAB detection kit was used as a color developer after the secondary antibody was combined, and finally, the percentage of positive cells was estimated with Image J analysis software [22]. All images were taken using an optical microscope.

Statistical Analysis

All data are presented as mean ± standard error of the mean (SEM). All charts show relevant data for at least 3 independent tests. SPSS 26.0 software was used to analyze the statistical analyses. Student’s t-test was used for between-group comparisons followed by a Tukey post-hoc test when an ANOVA revealed significance. A two (± tumor) by two (± CUMS) ANOVA with time as a repeated measure was used for the comparison of four experimental groups. Significance is defined as P<0.05 for all analysis.

CUMS induces depression-like behavior in BALB/c mice and C57BL/6 mice

The experimental flow chart is shown in Fig. 1A. In CUMS group mice, sucrose preference decreased (Fig. 1B, 1H), total locomotion diminished in OFT (Fig. 1C, 1I), prolonged immobility time (Fig. 1E, 1F, 1K, 1L), and lower body weights (Fig. 1G, 1M) compared to the control group. These results indicate that the depression model was successfully established in BALB/c mice and C57BL/6 mice.

The combination of tumors and CUMS exacerbated depression-like behavior in mice.

To investigate whether the mice in the tumor group exhibited anxiety-like and depressive-like behaviors and whether depression-like behaviors were more severe in the BCRD and LCRD[20], we performed behavioral assessments on tumor-bearing mice separately. In BALB/c mice, tumor-bearing decreased sucrose preference (Fig. 2A), prolonged immobility time of TST (Fig. 2D), and impaired spatial cognition (Fig. 2E), compared to the control group. Compared to the BC group, BCRD mice displayed more decreased sucrose preference in SPT (Fig. 2A), more diminished total locomotion in OFT (Fig. 2B&C), more prolonged immobility time (Fig. 2D), and severe spatial cognitive dysfunction (Fig. 2E). No significance in the number and stay time of mice entering the open arm between tumor-bearing mice and control mice. Meanwhile, we also assessed the change of SPT and TST of each mouse before and after bearing the tumor. The data showed both control and CUMS mice occurred obvious anhedonia and prolonged immobility time after tumor-bearing, and CUMS induced more individuals and greater variation depression in tumor-bearing mice (Fig. 2H, 2I).

In C57BL/6 mice, as the same, tumor-bearing decreased sucrose preference (Fig. 2K), diminished total locomotion (Fig. 2L), and reduced open arm entries and dwell time (Fig. 2N, 2O) compared to the control group. Compared to the LC group, LCRD mice displayed more decreased sucrose preference in SPT (Fig. 2K), more diminished total locomotion in OFT (Fig. 2L), decreased the number and stay time of mice entering the open arm (Fig. 2N, 2O). Whether comparing between groups or comparing before and after tumor-bearing, CUMS led to more severe depression-like behavior(Fig. 2P), consistent with breast cancer.

Chronic stress-induced impairment of hippocampal neurons in tumor-bearing mice.

It is reported that hippocampal neurons play a crucial role in depression [5, 23], and Chronic stress causes pathophysiological changes in the hippocampus, which can induce depression [11, 24]. As seen in Fig. 3, the results of Nissl and H&E staining showed that hippocampal neurons were full and clear with a tight and neat cellular arrangement in the control group mice. The Nissl bodies were clear, and no obvious neuron degeneration. The hippocampus neurons were damaged, irregularly arranged, and sparsely distributed, with a widened interstitium in CA1, CA2, and CA3 regions in both CUMS group and two tumor groups (BC and LC). There was a significant decrease in the number of Nissl bodies and a tendency for them to spread to the outer layer. In addition, CUMS aggravated irregular arrangement and sparse distribution in CA2 and CA3 hippocampal regions in tumor-bearing mice, and Nissl bodies were absent and there were obvious neuronal“escapes” and ablation. These results suggest that CUMS aggravates hippocampal neuronal damage in tumor-bearing mice. Western blotting results showed that PSD-95, GAP-43, and Syn were significantly lower in the CUMS group and the BC and LC group compared with the control group. However the interaction between the control group and the BCRD and LCRD group was not significant(Fig C and D, G and H).

Chronic stress accelerated tumor tumorigenesis and metastasis

Here, we used live mouse bioluminescence imaging to track tumor growth and metastasis in both models of mice. Fluorescence intensity obtained by in vivo imaging, and tumor visual morphology in vitro showed that the tumors in tumor-bearing mice suffered from CUMS were more severe than those without CUMS (Fig. 4A,4B,4E,4J,4K,4N). At the same time, the volume of the mammary glands the weight of the BCRD mice, and the weight of the lungs of the LCRD mice increased significantly (Fig. 4C,4D,4L). Tissue sections were prepared for pathologic analysis. H&E staining showed that more numerous and larger tumor foci with more dense tumor cells were observed both in BCRD and LCRD mice, and the core of the tumor showed a necrosis-like structure due to lack of nutrients. More scattered tumor-infiltrating cells were also observed in other residual normal tissue cells (Fig. 4H,4M).

The 4T1-Luc cells are reported to be a highly metastatic breast cancer cell line with a tendency to metastasize to the lung in vivo [25]. this phenomenon has indeed been observed by in vivo imaging (Fig. 4G). Furthermore, a greater number and size of metastases were discovered in breast cancer mice exposed to CUMS (Fig. 4F). The liver is a common priority metastasis site of lung cancer [26, 27]. and the bioluminescence imaging results were confirmed (Fig. 4O). As similar, more liver metastases were also observed in LCRD (Fig. 4P). Histopathologic results also showed that the cancer cell morphology in BCRD and LCRD mice metastases was more serious and deteriorated (Fig. 4I,4Q). The above results indicated that chronic stress was a high-risk factor for tumor metastasis.

Chronic stress led to a reduction in glycolysis within the brain tissues of tumor-bearing mice.

Studies have shown that brain plasticity is one of the pathogenic mechanisms of depression, and glycolytic metabolism is closely related to synaptic plasticity [28–30].

In BALB/c mice, BCRD group glucose metabolites ATP and pyruvate were significantly less than BC, while no difference in lactic acid (Fig. 6A-C). Glycolytic metabolic enzymes in the brain (HKI, PFKP, PKM2, PDH, and LDHA) were detected with the Western blot test. The levels of HKI and LDHA were decreased in CUMS mice, and tumor mice compared to the control group. However, there were no significant changes observed in PFKP and PKM2 expression, and the interaction between the control group and the BCRD group was not significant (Fig. 6D,6E).

In C57BL/6 mice, LCRD group glucose metabolites ATP and lactic acid were significantly less than LC, there was no significant difference in pyruvate levels (Fig. 6F-H). Western blot results showed that HKI and LDHA were significantly lower in the CUMS group and the LC group compared with the control group. The expression level of PFKP was not significant in the four groups of mice, and the interaction between the control group and the LCRD group was not significant (Fig. 6I, 6J). Overall, those results showed that CUMS may induce a decrease in glycolytic enzymes in the brains of mice.

Chronic stress augmented aerobic glycolysis within tumor tissues

Warburg effect is critical for the metabolic reprogramming of tumor cells [31, 32]. the uptake of glucose was enhanced, leading to an increase in lactate production and extracellular acidification rates [33]. It has been reported that CUMS induces adrenergic activation of LDHA to produce lactate, which promotes the growth of breast cancer [10, 11]. Therefore, we investigated the regulatory role of CUMS in glycolysis. As shown in Fig. 7, the tumor tissues of tumor-bearing mice(both BCRD and LCRD) pretreated by CUMS exhibited elevated levels of glycolysis products and key catalytic enzymes(Fig. 6A-C,6E,6F,6G-I,6K,6L). However, IHC detection results revealed the distribution pattern of HKII in BC and LC tissues is different. The distribution of HKII in BC tissues is relatively uniform, and HKII is mainly confined to superficial tumor tissues, while HKII in LC tissues is diffusely dispersed in tumor cells and surrounding tissues of normal lung tissues.

It has been reported that approximately 280 million people worldwide suffer from depression, and 800,000 of them die from depression each year [34–36]. Nearly 80% of depression patients are not diagnosed in time [36]. Animal and clinical studies have shown a link between emotional dysfunction and tumorigenesis [37]. Approximately 20%-30% of patients with advanced cancer develop clinically significant depression, and 15% suffer from severe anxiety disorders [38]. In this study, it was demonstrated that chronic stress can cause depression-like behavior and facilitated tumor genesis and metastasis of BC and LC, meanwhile, all the tumor-bearing mice exhibited depression-like behavior to different extents. In addition, Chronic stress is not only associated with depression but also with burnout and cognitive impairment [39]. Among 102 cancer survivors aged 25–79 years, approximately one-third had cognitive failures in daily life [40–42]. Our results suggest that chronic stress induces the production of depressive-like behaviors, reduces spatial cognition in mice, and induces mice to exhibit more severe depressive-like behaviors and cognitive dysfunction. These results are consistent with those reported in the literature [43].

Dysregulation of neuroplasticity and neuronal cell damage are thought to be key mediators in the pathogenesis of depression [30, 44, 45]. Our results also confirmed that CUMS induced neuronal damage and synaptic plasticity reduction in mice, which is consistent with the literature [46, 47]. Furthermore, cancer is intricately linked with neurological remodeling and dysfunction neurological-cancer interactions have the potential to modulate tumor growth, invasion, and metastasis dissemination[48]. tumor growth has been associated with substantial alterations in the hippocampus and a reduction in neuronal cell count, ultimately contributing to depressive symptoms [49]. Notably, Chronic stress is correlated with the activation of the neuroendocrine system, specifically the hypothalamic-pituitary-adrenal axis, and the sympathetic nervous system. Additionally, it leads to the release of stress hormones such as catecholamines and glucocorticoids [50]. The microenvironment is changed by the disruption of stress, neurotransmitters, and immune cells and promotes tumorigenesis and progression through a variety of mechanisms [37]. It was reported that the stimulation of β2-adrenergic receptors in PDAC cancer cells by noradrenaline induced by chronic stress leads to the production of autocrine and paracrine effects, thereby promoting tumor growth [51]. Our findings also validate the notion that tumors can induce neuronal cell damage and diminish synaptic plasticity in mice. Chronic stress exacerbates neuronal impairment and reduces the survival rate of mice with tumors.

The Warburg effect is considered to be a critical element in the reprogramming of energy metabolism in malignant tumors [31]. Chronic stress also plays an important role [10], and it promotes tumor growth and metastasis through multiple mechanisms [37]. HKII is the first irreversible enzyme of glycolysis that inhibits the activity of the PDH complex by phosphorylating S1 of PDHA293 and promotes the Warburg effect [52]. In addition to serving as an energetic metabolism substrate, lactate can be transported to neurons thereby sustaining neuronal function and exerting antidepressant effects [53, 54]. Additionally, the augmented Warburg effect in the hippocampus contributes to enhanced synaptic plasticity [55]. The glycolytic metabolites in the brain of each group of mice revealed a significant reduction in glycolytic activity within the brains of tumor-bearing mice compared to the control group, and chronic stress further exacerbated the impairment in glycolysis. Recent studies have shown that chronic stress accelerates the progression of colorectal cancer by boosting glycolysis via the CREB1/2-AR signaling pathway [10]. In a mouse model, chronic stress boosts adrenaline levels and encourages tumor growth by activating the LDHA/USP28/MYC/SLUG signaling axis [11]. our results also show that chronic stress induced higher expression of glycolytic metabolites in tumor tissue.

In conclusion, our findings consistently indicate chronic stress-induced anxiety-like and depression-like behaviors in mice, while also promoting the overproduction of lactic acid through increased aerobic glycolytic enzymes in tumor tissue. extracellular acidification to maintain the invasive growth of cancer cells and further exacerbate the progression and metastasis of BC and LC. The findings of this study contribute to a deeper understanding of the impact of metabolic remodeling on the pathogenesis of cancer-related depression. However, It was challenging to establish a strong connection between CUMS and glycolysis because of the small sample size, which limited the experiment's findings to examining changes in glycolysis in tumor progression under chronic stress rather than delving into the underlying mechanisms in detail. As a result, future related studies should concentrate on assessing glycolysis's significant contribution to the phenomenon of cancer-associated depression. In the meantime, because the cancer cell lines used in this study came from different places, different strains of mice were given different injections of cancer cells. It was discovered that this caused variations in the immune responses and stress levels in the male and female mice, which in turn led to variations in the model's experiment outcomes. Consequently, we plan to inject the cancer cells into the same strains of mice in future related studies.

Acknowledgments

We thank the Natural Science Foundation of Guang Dong Province for the generous funding of our studies. Moreover, we thank the National Natural Science Foundation of China for the generous funding of our studies.

Funding

This study was supported by the Natural Science Foundation of Guang Dong Province (2023A1515011343) and the National Natural Science Foundation of China (81903943).

Author Contributions

Conceptualization: H.Q.L, R.Z, and S.S.B. Primary writing and original draft preparation: Q.F.Q and S.Y.L. Editing: Y.X.Z, J.B, S.S.B. Visualization and supervision: L.A, L.Y, W.G, D.D, J.L.Z. All authors agreed to the version of the manuscript.

Data availability

Data generated or analyzed during this study are included in this published article (and its supplementary information files).

Ethics approval The animal study was reviewed and approved by Guangzhou University of Chinese Medicine.

Competing interests

The authors report no conflicts of interest.

Panjwani AA, Li ME (2021) Recent trends in the management of depression in persons with cancer. Current Opinion in Psychiatry 34: 448-459. DOI 10.1097/Yco.0000000000000727
Hauffman A, Alfonsson S, Bill-Axelson A, Bergkvist L, Forslund M, Mattsson S, von Essen L, Nygren P, Igelström H, Johansson B (2020) Cocreated internet-based stepped care for individuals with cancer and concurrent symptoms of anxiety and depression: Results from the U-CARE AdultCan randomized controlled trial. Psycho-oncology 29: 2012-2018. DOI 10.1002/pon.5489
Zheng Y, Wang N, Wang S, Zhang J, Yang B, Wang Z (2023) Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling. Journal of experimental & clinical cancer research : CR 42: 129. DOI 10.1186/s13046-023-02696-z
Zhou Q, Ding W, Qian Z, Jiang G, Sun C, Xu K (2020) Chronic Unpredictable Mild Stress Accelerates the Growth of Bladder Cancer in a Xenograft Mouse Model. Psychology research and behavior management 13: 1289-1297. DOI 10.2147/prbm.S288983
Li XM, Teng T, Yan W, Fan L, Liu XE, Clarke G, Zhu D, Jiang YL, Xiang YJ, Yu Y, et al. (2023) AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models. Transl Psychiat 13. DOI ARTN 200 10.1038/s41398-023-02486-3
Bortolato B, Hyphantis TN, Valpione S, Perini G, Maes M, Morris G, Kubera M, Köhler CA, Fernandes BS, Stubbs B, et al. (2017) Depression in cancer: The many biobehavioral pathways driving tumor progression. Cancer treatment reviews 52: 58-70. DOI 10.1016/j.ctrv.2016.11.004
Chida Y, Hamer M, Wardle J, Steptoe A (2008) Do stress-related psychosocial factors contribute to cancer incidence and survival? Nature clinical practice Oncology 5: 466-475. DOI 10.1038/ncponc1134
Dai S, Mo Y, Wang Y, Xiang B, Liao Q, Zhou M, Li X, Li Y, Xiong W, Li G, et al. (2020) Chronic Stress Promotes Cancer Development. Frontiers in oncology 10: 1492. DOI 10.3389/fonc.2020.01492
Pu C, Tian S, He S, Chen W, He Y, Ren H, Zhu J, Tang J, Huang X, Xiang Y, et al. (2022) Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin. Genes & diseases 9: 1024-1037. DOI 10.1016/j.gendis.2020.11.013
Guan Y, Yao W, Yu H, Feng Y, Zhao Y, Zhan X, Wang Y (2023) Chronic stress promotes colorectal cancer progression by enhancing glycolysis through β2-AR/CREB1 signal pathway. International journal of biological sciences 19: 2006-2019. DOI 10.7150/ijbs.79583
Cui B, Luo Y, Tian P, Peng F, Lu J, Yang Y, Su Q, Liu B, Yu J, Luo X, et al. (2019) Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. The Journal of clinical investigation 129: 1030-1046. DOI 10.1172/jci121685
Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11: 325-337. DOI 10.1038/nrc3038
Paul S, Ghosh S, Kumar S (2022) Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol 86: 1216-1230. DOI 10.1016/j.semcancer.2022.09.007
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891-899. DOI 10.1038/nrc1478
Hirschhaeuser F, Sattler UG, Mueller-Klieser W (2011) Lactate: a metabolic key player in cancer. Cancer research 71: 6921-6925. DOI 10.1158/0008-5472.Can-11-1457
Karnib N, El-Ghandour R, El Hayek L, Nasrallah P, Khalifeh M, Barmo N, Jabre V, Ibrahim P, Bilen M, Stephan JS, et al. (2019) Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases. Neuropsychopharmacol 44: 1152-1162. DOI 10.1038/s41386-019-0313-z
Yao S, Xu MD, Wang Y, Zhao ST, Wang J, Chen GF, Chen WB, Liu J, Huang GB, Sun WJ, et al. (2023) Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice. Nat Commun 14. DOI 10.1038/s41467-023-36209-5
Li N, Wang Q, Wang Y, Sun A, Lin Y, Jin Y, Li X (2019) Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis. Stress (Amsterdam, Netherlands) 22: 592-602. DOI 10.1080/10253890.2019.1617267
Zhan YH, Han JY, Xia J, Wang XM (2021) Berberine Suppresses Mice Depression Behaviors and Promotes Hippocampal Neurons Growth Through Regulating the miR-34b-5p/miR-470-5p/BDNF Axis. Neuropsych Dis Treat 17: 613-626. DOI 10.2147/Ndt.S289444
Casaril AM, Domingues M, Bampi SR, Lourenco DD, Smaniotto TA, Segatto N, Vieira B, Seixas FK, Collares T, Lenardao EJ, et al. (2020) The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl) selanyl]-1-methyl-1H-indole attenuates depression-like behavior and Cognitive impairment developed in a mouse model of breast tumor. Brain Behav Immun 84: 229-241. DOI 10.1016/j.bbi.2019.12.005
Yoshizaki K, Asai M, Hara T (2020) High-Fat Diet Enhances Working Memory in the Y-Maze Test in Male C57BL/6J Mice with Less Anxiety in the Elevated Plus Maze Test. Nutrients 12. DOI ARTN 2036 10.3390/nu12072036
Chen Z, Chen L, Sun B, Liu D, He Y, Qi L, Li G, Han Z, Zhan L, Zhang S, et al. (2021) LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway. Molecular metabolism 51: 101230. DOI 10.1016/j.molmet.2021.101230
Tunc-Ozcan E, Peng CY, Zhu YW, Dunlop SR, Contractor A, Kessler JA (2019) Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat Commun 10. DOI ARTN 3768 10.1038/s41467-019-11641-8
Li M, Sun X, Wang Z, Li Y (2023) Caspase-1 affects chronic restraint stress-induced depression-like behaviors by modifying GABAergic dysfunction in the hippocampus. Transl Psychiatry 13: 229. DOI 10.1038/s41398-023-02527-x
Li J, Wang S, Wang N, Zheng Y, Yang B, Wang X, Zhang J, Pan B, Wang Z (2021) Aiduqing formula inhibits breast cancer metastasis by suppressing TAM/CXCL1-induced Treg differentiation and infiltration. Cell communication and signaling : CCS 19: 89. DOI 10.1186/s12964-021-00775-2
Chang MM, Wu SZ, Yang SH, Wu CC, Wang CY, Huang BM (2021) FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer. Translational oncology 14: 101208. DOI 10.1016/j.tranon.2021.101208
Rosa-Caldwell ME, Brown JL, Lee DE, Wiggs MP, Perry RA, Haynie WS, Caldwell AR, Washington TA, Lo WJ, Greene NP (2020) Hepatic alterations during the development and progression of cancer cachexia. Appl Physiol Nutr Me 45: 500-512. DOI 10.1139/apnm-2019-0407
Zhao JL, Jiang WT, Wang X, Cai ZD, Liu ZH, Liu GR (2020) Exercise, brain plasticity, and depression. CNS neuroscience & therapeutics 26: 885-895. DOI 10.1111/cns.13385
Kandola A, Ashdown-Franks G, Hendrikse J, Sabiston CM, Stubbs B (2019) Physical activity and depression: Towards understanding the antidepressant mechanisms of physical activity. Neuroscience and Biobehavioral Reviews 107: 525-539. DOI 10.1016/j.neubiorev.2019.09.040
Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M (2022) Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatr 27: 2689-2699. DOI 10.1038/s41380-022-01520-y
Fukushi A, Kim HD, Chang YC, Kim CH (2022) Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells. International journal of molecular sciences 23. DOI ARTN 10037 10.3390/ijms231710037
Zhang Y, Zhai Z, Duan J, Wang X, Zhong J, Wu L, Li A, Cao M, Wu Y, Shi H, et al. (2022) Lactate: The Mediator of Metabolism and Immunosuppression. Frontiers in endocrinology 13: 901495. DOI 10.3389/fendo.2022.901495
Jiang JX, Roman J, Xu HN, Li LZ (2021) An Observation on Enhanced Extracellular Acidification and Lactate Production Induced by Inhibition of Lactate Dehydrogenase A. Adv Exp Med Biol 1269: 163-167. DOI 10.1007/978-3-030-48238-1_26
Price RB, Duman R (2020) Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatr 25: 530-543. DOI 10.1038/s41380-019-0615-x
Zheng ZW, Guo C, Li M, Yang L, Liu PY, Zhang XL, Liu YQ, Guo XN, Cao SX, Dong YY, et al. (2022) Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron 110: 1400-+. DOI 10.1016/j.neuron.2022.01.011
Chen ZW, Gu J, Lin S, Xu Z, Xu H, Zhao JJ, Feng PS, Tao Y, Chen SH, Wang P (2023) Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway. J Ethnopharmacol 300. DOI ARTN 115719 10.1016/j.jep.2022.115719
Hong H, Ji M, Lai D (2021) Chronic Stress Effects on Tumor: Pathway and Mechanism. Frontiers in oncology 11: 738252. DOI 10.3389/fonc.2021.738252
Asher A, Shirazipour CH, Capaldi JM, Kim S, Diniz M, Jones B, Wertheimer J (2023) A 6-Week Program to Strengthen Resiliency Among Women With Metastatic Cancer: A Randomized Clinical Trial. Oncologist. DOI 10.1093/oncolo/oyad091
Hussenoeder FS, Conrad I, Pabst A, Luppa M, Stein J, Engel C, Zachariae S, Zeynalova S, Yahiaoui-Doktor M, Glaesmer H, et al. (2022) Different Areas of Chronic Stress and Their Associations with Depression. International journal of environmental research and public health 19. DOI 10.3390/ijerph19148773
Boleková V, Chlebcová V (2023) Predictors of cognitive failures in cancer survivors. Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti 36: 45-53. DOI 10.48095/ccko202345
Park JH, Jung YS, Jung YM, Bae SH (2019) The role of depression in the relationship between cognitive decline and quality of life among breast cancer patients. Support Care Cancer 27: 2707-2714. DOI 10.1007/s00520-018-4546-x
Cao Y, Chen X, Xie H, Zou L, Hu LJ, Zhou XJ (2017) Correlation between Electroencephalogram Alterations and Frontal Cognitive Impairment in Esophageal Cancer Patients Complicated with Depression. Chinese medical journal 130: 1785-1790. DOI 10.4103/0366-6999.211552
Di Iulio F, Cravello L, Shofany J, Paolucci S, Caltagirone C, Morone G (2019) Neuropsychological disorders in non-central nervous system cancer: a review of objective cognitive impairment, depression, and related rehabilitation options. Neurological Sciences 40: 1759-1774. DOI 10.1007/s10072-019-03898-0
Liu W, Ge TT, Leng YS, Pan ZX, Fan JE, Yang W, Cui RJ (2017) The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural Plast 2017. DOI Artn 6871089 10.1155/2017/6871089
Du T, Li G, Luo H, Pan Y, Xu Q, Ma K (2021) Hippocampal alpha-synuclein mediates depressive-like behaviors. Brain Behav Immun 95: 226-237. DOI 10.1016/j.bbi.2021.03.020
Parekh PK, Johnson SB, Liston C (2022) Synaptic Mechanisms Regulating Mood State Transitions in Depression. Annu Rev Neurosci 45: 581-601. DOI 10.1146/annurev-neuro-110920-040422
Appelbaum LG, Shenasa MA, Stolz L, Daskalakis Z (2023) Synaptic plasticity and mental health: methods, challenges and opportunities. Neuropsychopharmacol 48: 113-120. DOI 10.1038/s41386-022-01370-w
Winkler F, Venkatesh HS, Amit M, Batchelor T, Demir IE, Deneen B, Gutmann DH, Hervey-Jumper S, Kuner T, Mabbott D, et al. (2023) Cancer neuroscience: State of the field, emerging directions. Cell 186: 1689-1707. DOI 10.1016/j.cell.2023.02.002
Zhu Q, Meng P, Han Y, Yang H, Yang Q, Liu Z, Wang Y, Long M (2022) Luteolin Induced Hippocampal Neuronal Pyroptosis Inhibition by Regulation of miR-124-3p/TNF-α/TRAF6 Axis in Mice Affected by Breast-Cancer-Related Depression. Evidence-based complementary and alternative medicine : eCAM 2022: 2715325. DOI 10.1155/2022/2715325
Tian W, Liu Y, Cao C, Zeng Y, Pan Y, Liu X, Peng Y, Wu F (2021) Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Frontiers in cell and developmental biology 9: 777018. DOI 10.3389/fcell.2021.777018
Hanahan D, Monje M (2023) Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell 41: 573-580. DOI 10.1016/j.ccell.2023.02.012
Luo F, Li Y, Yuan F, Zuo J (2019) Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 31: 521-532. DOI 10.21147/j.issn.1000-9604.2019.03.14
Powell CL, Davidson AR, Brown AM (2020) Universal Glia to Neurone Lactate Transfer in the Nervous System: Physiological Functions and Pathological Consequences. Biosensors-Basel 10. DOI ARTN 183 10.3390/bios10110183
Carrard A, Elsayed M, Margineanu M, Boury-Jamot B, Fragnière L, Meylan EM, Petit JM, Fiumelli H, Magistretti PJ, Martin JL (2018) Peripheral administration of lactate produces antidepressant-like effects. Mol Psychiatry 23: 392-399. DOI 10.1038/mp.2016.179
Yang SQ, Tang YY, Zeng D, Tian Q, Wei HJ, Wang CY, Zhang P, Chen YJ, Zou W, Tang XQ (2022) Sodium hydrosulfide reverses β(2)-microglobulin-induced depressive-like behaviors of male Sprague-Dawley rats: Involving improvement of synaptic plasticity and enhancement of Warburg effect in hippocampus. Behavioural brain research 417: 113562. DOI 10.1016/j.bbr.2021.113562

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Chronic Stress Enhances Glycolysis and Promotes Tumorigenesis

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Version 1

Abstract

Figures

Key messages

Introduction

Material and Methods

Cell culture

Animals

Chronic unpredictable mild stress experiment

Establishment of tumor orthotopic transplantation

Behavior assessments

Western Blot

Glycolytic metabolites measurement

Hematoxylin and eosin staining (H&E), Nissl staining

Immunohistochemistry

Statistical Analysis

Results

CUMS induces depression-like behavior in BALB/c mice and C57BL/6 mice

Chronic stress accelerated tumor tumorigenesis and metastasis

Chronic stress augmented aerobic glycolysis within tumor tissues

Discussion

Declarations

References

Supplementary Files

Status:

Version 1