The anti-neoplastic effects of metformin modulate the acquired phenotype of fbroblast cells in the breast cancer-normal fbroblast co-culture system

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and metastasis.In order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal fibroblasts.We created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our theory.Moreover,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate secretion.These results were validated using the monoculture of each group separately as a control.In this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both cells.However,MCT4 and lactate stayed high after treatment with metformin.In conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal fibroblasts.Metformin,however,may change this state and affect fibroblasts'acquired phenotypes.Moreover,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.

Immunologic tumor microenvironment modulators for turning cold tumors hot

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment(TME).Hot tumors,characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors(ICIs),stand in stark contrast to cold tumors,which lack immune infiltration and remain resistant to therapy.To overcome immune evasion mechanisms employed by tumor cells,novel immunologic modulators have emerged,particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1).These agents disrupt inhibitory signals and reactivate the immune system,transforming cold tumors into hot ones and promoting effective antitumor responses.However,challenges persist,including primary resistance to immunotherapy,autoimmune side effects,and tumor response heterogeneity.Addressing these challenges requires innovative strategies,deeper mechanistic insights,and a combination of immune interventions to enhance the effectiveness of immunotherapies.In the landscape of cancer medicine,where immune cold tumors represent a formidable hurdle,understanding the TME and harnessing its potential to reprogram the immune response is paramount.This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies,offering hope for patients with immune-resistant tumors.