Targeting the Lymphatic-Inflammatory Axis in Bladder Cancer: A Comprehensive Review of Molecular Mechanisms and the Therapeutic Potential of $\alpha$-Tomatine

Abstract

Background: Bladder cancer (BCa) remains a significant global health challenge, characterized by high recurrence rates and significant mortality associated with lymph node metastasis (LNM). The spread of tumor cells through the lymphatic system is driven by lymphangiogenesis, a process heavily regulated by the Vascular Endothelial Growth Factor-C (VEGF-C)/VEGFR-3 axis and exacerbated by chronic inflammation within the tumor microenvironment (TME). Despite advances in surgical and chemotherapeutic interventions, effective strategies to specifically inhibit metastatic dissemination are lacking.

Methods: This narrative review synthesizes current literature regarding the molecular drivers of BCa metastasis and the pharmacological potential of natural steroidal alkaloids. We analyzed data focusing on the interplay between inflammatory signaling (NF-$\kappa$B/MAPK) and lymphangiogenic factors, alongside the specific bioactivity of $\alpha$-tomatine.

Results: The literature confirms that VEGF-C and PDGF-BB are critical promoters of lymphatic vessel density in BCa. Furthermore, chronic activation of the NF-$\kappa$B pathway in tumor-associated immune cells fuels the secretion of these lymphangiogenic factors. Emerging evidence highlights $\alpha$-tomatine, a glycoalkaloid found in tomatoes, as a potent dual-inhibitor. $\alpha$-Tomatine suppresses inflammation by blocking MAPK/NF-$\kappa$B signaling and induces cancer cell apoptosis via Autophagy/Beclin-1 and Wnt/$\beta$-catenin modulation.

Conclusion: Targeting the intersection of inflammation and lymphangiogenesis offers a promising therapeutic avenue. $\alpha$-Tomatine represents a high-potential lead compound that may suppress BCa metastasis by severing the inflammatory support network required for lymphatic expansion. Future research should focus on optimizing the bioavailability of this alkaloid for clinical application.

Keywords:

Bladder Cancer, Lymphangiogenesis, VEGF-C

References

Lopez-Beltran A, Cookson MS, Guercio BJ, Cheng L. Advances in diagnosis and treatment of bladder cancer. Bmj. 2024; 384.

DeGeorge KC, Holt HR, Hodges SC. Bladder Cancer: Diagnosis and Treatment. Am Fam Physician. 2017; 96: 507-14.

Gill E, Perks CM. Mini-review: current bladder cancer treatment—the need for improvement. International Journal of Molecular Sciences. 2024; 25: 1557.

Jones D, Pereira ER, Padera TP. Growth and Immune Evasion of Lymph Node Metastasis. Front Oncol. 2018; 8: 36.

Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol. 2012; 61: 1039-47.

Olszewski WL. The lymphatic system in body homeostasis: physiological conditions. Lymphat Res Biol. 2003; 1: 11-21; discussion -4.

Martinez-Corral I, Olmeda D, Dieguez-Hurtado R, Tammela T, Alitalo K, Ortega S. In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis. Proc Natl Acad Sci U S A. 2012; 109: 6223-8.

Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001; 20: 672-82.

Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004; 6: 333-45.

Kong D, Zhou H, Neelakantan D, Hughes CJ, Hsu JY, Srinivasan RR, et al. VEGF-C mediates tumor growth and metastasis through promoting EMT-epithelial breast cancer cell crosstalk. Oncogene. 2021; 40: 964-79.

Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001; 7: 186-91.

Rinderknecht M, Villa A, Ballmer-Hofer K, Neri D, Detmar M. Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-C block its interaction with VEGF receptor-2 and 3. PLoS One. 2010; 5: e11941.

He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002; 94: 819-25.

Bornstein P, Sage EH. Thrombospondins. Methods Enzymol. 1994; 245: 62-85.

Yang Y, Wang D, Li Q, He J, Wang B, Li J, et al. Immune-enhancing activity of aqueous extracts from Artemisia rupestris L. via MAPK and NF-kB pathways of TLR4/TLR2 downstream in dendritic cells. Vaccines. 2020; 8: 525.

Wang Y, Mou C, Huang L, Su J, You L, Zhang J, et al. The ethanolic extract of Rhaphidophora peepla prevents inflammation by inhibiting the activation of Syk/AKT/NF-κB and TAK1/MAPK/AP-1. Phytomedicine. 2025; 136: 156339.

Faria-Silva C, de Sousa M, Carvalheiro MC, Simoes P, Simoes S. α-tomatine and the two sides of the same coin: an anti-nutritional glycoalkaloid with potential in human health. Food Chem. 2022; 391: 133261.

Fullerton JN, Gilroy DW. Resolution of inflammation: a new therapeutic frontier. Nat Rev Drug Discov. 2016; 15: 551-67.

Allijn IE, Brinkhuis RP, Storm G, Schiffelers RM. Anti-inflammatory properties of plant derived natural products - a systematic review. Curr Med Chem. 2019; 26: 4506-36.

Zhang B, Wang T, Xu C, Yuan Y. Dual-edged mechanisms of α-Tomatine in hepatocellular carcinoma by suppression of Wnt/β-Catenin signaling versus RelB-driven resistance in tumor therapy. Front Pharmacol. 2025; 16: 1616975.

Wu H, Li W, Wang T, Rong Y, He Z, Huang S, et al. α-Tomatine, a novel early-stage autophagy inhibitor, inhibits autophagy to enhance apoptosis via Beclin-1 in Skov3 cells. Fitoterapia. 2021; 152: 104911.

Kozukue N, Han JS, Lee KR, Friedman M. Dehydrotomatine and α-tomatine content in tomato fruits and vegetative plant tissues. J Agric Food Chem. 2004; 52: 2079-83.

Bai R, Yao C, Zhong Z, Ge J, Bai Z, Ye X, et al. Discovery of natural anti-inflammatory alkaloids: Potential leads for the drug discovery for the treatment of inflammation. Eur J Med Chem. 2021; 213: 113165.

Manoharan R, Nair CS, Eissa N, Cheng H, Ge P, Ren M, et al. Therapeutic potential of solanum alkaloids with special emphasis on cancer: a comprehensive review. Drug Des Devel Ther. 2024; 18: 3063-74.

Serrati S, Porcelli L, Guida S, Ferretta A, Iacobazzi RM, Cocco T, et al. Tomatine displays antitumor potential in in vitro models of metastatic melanoma. Int J Mol Sci. 2020; 21: 5243.