Probiotics in Pancreatic Cancer Treatment
Pancreatic cancer is one of the most dangerous malignant diseases with a high mortality rate. Only 24% of patients survive after one year, and a mere 9% live up to five years post-diagnosis [1], while most patients have a life expectancy of about 8–13 months [2]. The commonly used treatment method is surgical tumor removal. However, only a minority (<20%) of patients meet the criteria for tumor removal due to the rapid metastasis of pancreatic cancer and its condition at the time of detection.
Recent studies on beneficial microorganisms – probiotics – have shed light on how probiotics can impact the development and treatment of cancer. Specifically, in pancreatic epithelial tissue cancer, probiotics have been demonstrated to produce intermediates that counteract cell growth, reducing the number of cancer cells and tissue damage while inhibiting the transformation and metastasis of malignant cells within the pancreatic cancer cells [3].
Mechanism and Applications of Probiotics in Pancreatic Cancer Treatment
One type of probiotic utilized is Probiotic Aspergillus oryzae. During cultivation, the Heptelidic acid secreted by Aspergillus oryzae can circulate throughout the intestine and enter the host body. Subsequently, it travels to the pancreas through the MAPK p38 signaling pathway, inhibiting pancreatic cancer growth (Figure 1) [4-6]. Furthermore, some studies have indicated that the rapid deterioration of pancreatic cancer is related to Porphyromonas gingivalis, a bacteria causing oral diseases within the digestive system (gum inflammation, periodontal diseases, etc.). However, combining antibiotic treatment with probiotics significantly reduces the number and damage caused by pancreatic cancer cells and decreases transformation and metastasis [4,6]. Antibiotic treatments can cause unwanted side effects in patients. Treatment combined with probiotics may reduce some of these side effects by restoring beneficial microbiota [7,8]. The inhibitory effects of probiotics on cancer cell manifestations could be considered a promising, supplementary treatment method for immune checkpoint inhibitors for selected pancreatic cancer patients in the future.
Figure 1: Mechanism of probiotics in inhibiting pancreatic tumor activity
Clinical Trials and Recommendations on the Use of Probiotics in Treatment
Extensive research supports the multifaceted role of probiotics in preventing pancreatic cancer by controlling pancreatitis and various risk factors such as diabetes, pancreatic necrosis, infections, and obesity. However, current data are insufficient to conclude the effects of probiotics on pancreatic cancer due to limited trials and inconsistencies [7]. Using gut probiotics may prevent infection complications. The preventive effects of treating severe pancreatitis patients with probiotics were predicted and studied. In a previous study, the authors conducted research on 298 patients predicted to have severe pancreatitis within 72 hours of symptom onset, providing a multi-strain probiotic product or placebo via the intestine twice daily for 28 days [9]. This study was registered under the number ISRCTN38327949. In patients predicted with severe pancreatitis, prophylactic treatment with probiotics with a specific combination of probiotic strains did not reduce the risk of infection complications and was associated with an increased risk of mortality in severe pancreatitis patients. Therefore, preventive treatment for patients at risk of pancreatitis or pancreatic cancer should involve a specific combination of beneficial bacteria and appropriate dosages [10].
However, the effectiveness of probiotics varies based on the species and specific strains, and even a single strain of probiotics might exert its effects through multiple pathways in preventing pancreatic cancer. Newly emerging data suggest synbiotics are more effective than prebiotics or single probiotics. Many in vivo studies, especially in humans, need to be conducted to further clarify and confirm the potential role of probiotics, prebiotics, and synbiotics in preventing pancreatic cancer. There is no longer any doubt that research investigating the role of probiotics in preventing pancreatic cancer is still in its infancy. In conclusion, much remains to be understood about the role of probiotics in pancreatic cancer, but a promising future for preventive and definitive treatment methods is on the horizon.
References:
1. Rawla, Prashanth, Tagore Sunkara, and Vinaya Gaduputi. “Epidemiology of pancreatic cancer: global trends, etiology and risk factors.” World journal of oncology10, no. 1 (2019): 10-27.
2. Hariharan, Deepak, A. Saied, and H. M. Kocher. “Analysis of mortality rates for pancreatic cancer across the world.” Hpb10, no. 1 (2008): 58-62.
3. Panebianco, Concetta, Annacandida Villani, Federica Pisati, Fabrizio Orsenigo, Marynka Ulaszewska, Tiziana Pia Latiano, Adele Potenza et al. “Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models.” Biomedicine & Pharmacotherapy151 (2022): 113163.
4. Jan, Ming-Shiou, Wan-Ting Chen, Yu-Jen Chen, Chia-Wei Lin, Wen-Wei Chang, Chung-Hung Tsai, Jia-Shiou Peng, and Li-Jin Hsu. “Probiotics ameliorate Porphyromonas gingivalis-promoted pancreatic cancer progression in oncogenic Kras transgenic mice.” Cancer Research77, no. 13_Supplement (2017): 235-235.
5. Konishi, Hiroaki, Shotaro Isozaki, Shin Kashima, Kentaro Moriichi, Satoshi Ichikawa, Kazuki Yamamoto, Chikage Yamamura et al. “Probiotic Aspergillus oryzae produces anti-tumor mediator and exerts anti-tumor effects in pancreatic cancer through the p38 MAPK signaling pathway.” Scientific Reports11, no. 1 (2021): 11070.
6. Chen, Shan-Ming, Li-Jin Hsu, Hsiang-Lin Lee, Ching-Pin Lin, Szu-Wei Huang, Caucasus Jun-Lin Lai, Chia-Wei Lin et al. “Lactobacillus attenuate the progression of pancreatic cancer promoted by Porphyromonas gingivalis in K-RASG12D transgenic mice.” Cancers12, no. 12 (2020): 3522.
7. Singhal, Barkha, Ankita Mukherjee, and Shubham Srivastav. “Role of probiotics in pancreatic cancer prevention: the prospects and challenges.” Advances in Bioscience and Biotechnology 7, no. 11 (2016): 468-500.
8. Panebianco, Concetta, Federica Pisati, Maria Ulaszewska, Annapaola Andolfo, Annacandida Villani, Federica Federici, Manna Laura et al. “Tuning gut microbiota through a probiotic blend in gemcitabine‐treated pancreatic cancer xenografted mice.” Clinical and Translational Medicine11, no. 11 (2021).
9. Besselink, Marc GH, Hjalmar C. van Santvoort, Erik Buskens, Marja A. Boermeester, Harry van Goor, Harro M. Timmerman, Vincent B. Nieuwenhuijs et al. “Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.” The Lancet371, no. 9613 (2008): 651-659.
10. Besselink, Marc G., Hjalmar C. van Santvoort, Willem Renooij, Martin B. de Smet, Marja A. Boermeester, Kathelijn Fischer, Harro M. Timmerman et al. “Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis.” Annals of surgery250, no. 5 (2009): 712-719.