Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression.

Colorectal cancer (CRC) remains one of the most commonly diagnosed and deadliest types of cancer worldwide. CRC displays a desmoplastic reaction (DR) that has been inversely associated with poor prognosis; less DR is associated with a better prognosis. This reaction generates excessive connective tissue, in which cancer-associated fibroblasts (CAFs) are critical cells that form a part of the tumor microenvironment. CAFs are directly involved in tumorigenesis through different mechanisms. However, their role in immunosuppression in CRC is not well understood, and the precise role of signal transducers and activators of transcription (STATs) in mediating CAF activity in CRC remains unclear. Among the myriad chemical and biological factors that affect CAFs, different cytokines mediate their function by activating STAT signaling pathways. Thus, the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors. Here, we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Helminth-derived molecules improve 5-fluorouracil treatment on experimental colon tumorigenesis.

Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-ß, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of ß-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.

Periodontitis exacerbation during pregnancy in mice: Role of macrophage migration inhibitory factor as a key inductor.

OBJECTIVE: The present study was designed to investigate the role of macrophage migration inhibitory factor (MIF) in the exacerbation of pregestational periodontal disease (PGPD). BACKGROUND: Periodontitis (PT) is a severe stage of periodontal disease characterized by inflammation of the supporting tissues of the teeth, which usually worsens during pregnancy. MIF is a proinflammatory cytokine that is significantly elevated in periodontitis, both at the beginning and at the end of pregnancy. Although periodontitis usually presents with greater severity during pregnancy, the participation of MIF in the evolution of periodontitis has not been established. METHODS: To analyze the relevance of MIF in the exacerbation of PGPD, we employed a model of PGPD in WT and Mif-/- mice, both with a BALB/c genetic background. PT was induced with nylon suture ligatures placed supramarginally around the second upper right molar. For PGPD, PT was induced 2 weeks before mating. We evaluated histological changes and performed histometric analysis of the clinical attachment loss, relative expression of MMP-2 and MMP-13 by immunofluorescence, and relative expression of the cytokines mif, tnf-α, ifn-γ, and il-17 by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our data revealed that periodontal tissue from PGPD WT mice produced a twofold increase in MIF compared with PT WT mice. Moreover, the evolution of periodontitis in Mif-/- mice was less severe than in PGDP WT mice. Periodontal tissue from Mif-/- mice with PGPD produced 80% less TNF-α and no IFN-γ, as well as 50% lower expression of matrix metalloproteinase (MMP)-2 and 25% less MMP-13 compared to WT PGDP mice. CONCLUSIONS: Our study suggests that MIF plays an important role in the exacerbation of periodontitis during pregnancy and that MIF is partially responsible for the inflammation associated with the severity of periodontitis during pregnancy.

Macrophage Migration Inhibitory Factor (MIF) is a Key Player in Dry Eye Disease.

PURPOSE: To explore the role of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF), in a murine model of dry eye disease (DED). METHODS: The role of MIF on DED was determined using genetically MIF deficient mice and pharmacological inhibition of MIF. DED was induced with 0.5 mg of scopolamine via subcutaneous injection in wild type (WT) and mice lacking MIF (Mif-/-), three times a day for 21 days. DED signs, tear volume, ferning pattern and cytology impression were evaluated. Also, eye tissues were collected to determine transcripts of key inflammatory mediators and histopathological damage. In a second set of experiments, we neutralized MIF with ISO-1, an isozaxiline-derivative MIF tautomerase activity-inhibiting small molecule in WT mice, following an acute DED model for 10 days. ISO-1 was given starting on day 3 after DED induction and signs were evaluated, including a recovery phase in both experimental approaches. RESULTS: When compared to WT, Mif-/- mice showed attenuated signs of DED like preserved mucin pattern and increased tear volume. Also, Mif-/- mice maintained conjunctival epithelial cells and less corneal damage, associated with lower levels of TNFα and IL-1ß. At recovery phase, Mif-/- mice presented improved signs. Interestingly, in cornea and conjunctiva the absence of MIF selectively downregulated the transcription of inflammatory enzymes like inos and nox4 whereas displayed enhanced transcripts of il-4, il-13, tgfß and cox2. Finally, pharmacological inhibition of MIF using ISO-1, replicated the above findings in the mouse model. CONCLUSION: MIF is a central positive mediator of the inflammatory process in experimental DED, thus, targeting MIF could be used as a novel therapy in ocular surface inflammatory pathologies.

Molecular transition of SARS-CoV-2 from critical patients during the first year of the COVID-19 pandemic in Mexico City.

Background: The SARS-CoV-2 virus has caused unprecedented mortality since its emergence in late 2019. The continuous evolution of the viral genome through the concerted action of mutational forces has produced distinct variants that became dominant, challenging human immunity and vaccine development. Aim and methods: In this work, through an integrative genomic approach, we describe the molecular transition of SARS-CoV-2 by analyzing the viral whole genome sequences from 50 critical COVID-19 patients recruited during the first year of the pandemic in Mexico City. Results: Our results revealed differential levels of the evolutionary forces across the genome and specific mutational processes that have shaped the first two epidemiological waves of the pandemic in Mexico. Through phylogenetic analyses, we observed a genomic transition in the circulating SARS-CoV-2 genomes from several lineages prevalent in the first wave to a dominance of the B.1.1.519 variant (defined by T478K, P681H, and T732A mutations in the spike protein) in the second wave. Conclusion: This work contributes to a better understanding of the evolutionary dynamics and selective pressures that act at the genomic level, the prediction of more accurate variants of clinical significance, and a better comprehension of the molecular mechanisms driving the evolution of SARS-CoV-2 to improve vaccine and drug development.

Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies.

In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.

Role of a 49 kDa Trypanosoma cruzi Mucin-Associated Surface Protein (MASP49) during the Infection Process and Identification of a Mammalian Cell Surface Receptor.

Trypanosoma cruzi is the etiologic agent of Chagas disease, a parasitic disease of great medical importance on the American continent. Trypomastigote infection's initial step in a mammalian host is vital for the parasite's life cycle. A trypomastigote's surface presents many molecules, some of which have been proposed to be involved in the infection process, including a glycoprotein family called mucin-associated surface proteins (MASPs). This work describes a 49-kDa molecule (MASP49) that belongs to this family and is expressed mainly on the surfaces of amastigotes and trypomastigotes but can be found in extracts and the membrane-enriched fractions of epimastigotes. This protein is partially GPI-anchored to the surface and has a role during the internalization process, since its blockade with specific antibodies decreases parasite entry into Vero cells by 62%. This work shows that MASP49 binds to peritoneal macrophages and rat cardiomyocytes, undergoes glycosylation via galactose N-acetylgalactosamine, and can attach to the macrophage murine C-type lectin receptor (mMGL). These results suggest that MASP49 can be considered a virulence factor in T. cruzi, and a better understanding of its role in the infection process is necessary.

Dual activation profile of monocytes is associated with protection in Mexican patients during SARS-CoV-2 disease.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been one of the most catastrophic diseases observed in recent years. It has reported nearly 550 million cases worldwide, with more than 6.35 million deaths. In Mexico, an increased incidence and mortality of this disease were observed, where the immune response has been involved in the magnitude and severity. A critical version of the disease is accompanied by hyperinflammatory responses, with cytokine and defective cellular responses. A detailed understanding of the role of molecules and cells in the immune response during COVID-19 disease may help to generate effective protection mechanisms, improving those we already have. Here we analyzed blood samples obtained from patients at the Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI), Mexico, which were classified according to living guidance for clinical management of COVID-19 by the World Health Organization: asymptomatic, mild, severe, and critical disease. We observed increased interleukin (IL)-6 levels and a T-CD8+ and T-CD4+ cell reduction correlated with the critical disease version. Importantly, here, we described a significant reduction of CD11b+CD45highCD14low monocytes during severe disease, which displayed a non-classical profile, expressing IL-10, transforming growth factor (TGF)-ß, and indoleamine 2,3-dioxygenase (IDO)1 molecule. Moreover, CD11b+CD45highCD14low monocytes obtained from infected one-dose vaccinated patients (Pfizer® vaccine) who suffered minimal symptoms showed simultaneously a dual classical and no-classical profile expressing pro- and anti-inflammatory cytokines. These results suggest that blood monocytes expressing a dual pro- and anti-inflammatory profile might be a predictive marker for protection in the Mexican population during COVID-19 disease. KEY POINTS : • Exacerbated immune response is associated with COVID-19 severe disease. • Dual monocyte activation profile is crucial for predicting protection during COVID-19. • Vaccination is crucial to induce the dual activation profile in monocytes.

Macrophage migration inhibitory factor contributes to immunopathogenesis during Plasmodium yoelii 17XL infection.

Macrophage migration inhibitory factor (MIF) is a cytokine recognized regulator of the inflammatory immune response associated with several immune cells that produce inflammatory cytokines such as IL-1ß, IL-6, IL-12, IL-18, and TNF-α. This study aimed to understand the effect of MIF on the immune response and pathogenesis during Plasmodium infection. Wild-type (Wt) and MIF knockout (Mif -/-) mice were intravenously infected with 1×103 Plasmodium yoelii (Py) 17XL-parasitized red blood cells. Our data showed that Py17XL-infected Wt mice died 11 days postinfection, while Mif -/- mice showed reduced parasitemia and an increase in their survival at day 11 up to 58%, importantly they succumb up to day 21 postinfection. The increased survival rate in Mif -/- mice was associated with less severe cachexia and anemia as a result of a mixed Th1/Th2 cytokine profile, high levels of IL-12, IL-17/IL-4, and IL-10 in serum; and high levels of IL-4 and IL-10, and low levels of IFN-γ in spleen cells compared to Py17XL infected Wt mice. Moreover, macrophages (Mφs) from Mif -/- mice exhibited higher concentrations of IL-10 and IL-12 and reduced levels of TNF-α and nitric oxide (NO) compared to Py17XL-infected Wt mice. These results demonstrate that MIF has an important role in regulating the immune response associated with host pathogenesis and lethality, which is relevant to consider in preventing/reducing complications in Plasmodium infections.

Characterisation of Macrophage Polarisation in Mice Infected with Ninoa Strain of Trypanosoma cruzi.

Macrophages (MΦ) play a key role in the development of the protective immune response against Trypanosoma cruzi infection. To determine the role of MΦ subtypes M1 and M2 in the development of immunity against the Mexican strain of T. cruzi (Ninoa strain), we have analysed in a time course the infection and characterised the M1 and M2 subtypes in two mouse models, BALB/c and C57BL/6. After infection, BALB/c mice developed an increased blood parasite load and the parasites were cleared from the blood one week later than in C57BL/6 mice. However, similar cellular infiltrate and cardiac alterations were observed between BALB/c and C57BL/6 mice. At 36 days, the T. cruzi infection differentially modulated the expression of immune cells, and both the BALB/c and C57BL/6 mice significantly reduced TCD4+ cells. However, BALB/c mice produced significantly more TCD8+ than C57BL/6 mice in the spleen and lymph nodes. Furthermore, BALB/c mice produce significantly more MΦ in the spleen, while C57BL/6 produce similar levels to uninfected mice. The M1 MΦ ratio increased significantly at 3-5 days post-infection (dpi), but then decreased slightly. On the contrary, the M2 MΦ were low at the beginning of the infection, but the proportion of M1 and M2 MΦ at 36 dpi was similar. Importantly, the MΦ subtypes M2c and M2d significantly increased the induction of tissue repair by the end of the acute phase of the infection. These results indicate that the Ninoa strain has developed strategies to modulate the immune response, with fine differences depending on the genetic background of the host.

Recruitment of M1 Macrophages May Not Be Critical for Protection against Colitis-Associated Tumorigenesis.

A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480+TLR2+STAT1+) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα-/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis.

Influence of Gestational Hormones on the Bacteria-Induced Cytokine Response in Periodontitis.

Periodontitis is an inflammatory disease that affects the supporting structures of teeth. The presence of a bacterial biofilm initiates a destructive inflammatory process orchestrated by various inflammatory mediators, most notably proinflammatory cytokines, which are upregulated in the gingival crevicular fluid, leading to the formation of periodontal pockets. This represents a well-characterized microbial change during the transition from periodontal health to periodontitis; interestingly, the gestational condition increases the risk and severity of periodontal disease. Although the influence of periodontitis on pregnancy has been extensively reviewed, the relationship between pregnancy and the development/evolution of periodontitis has been little studied compared to the effect of periodontitis on adverse pregnancy outcomes. This review is aimed at summarizing the findings on the pregnancy-proinflammatory cytokine relationship and discussing its possible involvement in the development of periodontitis. We address (1) an overview of periodontal disease, (2) the immune response and possible involvement of proinflammatory cytokines in the development of periodontitis, (3) how bone tissue remodelling takes place with an emphasis on the involvement of the inflammatory response and metalloproteinases during periodontitis, and (4) the influence of hormonal profile during pregnancy on the development of periodontitis. Finally, we believe this review may be helpful for designing immunotherapies based on the stage of pregnancy to control the severity and pathology of periodontal disease.

Autophagy inhibition in breast cancer cells induces ROS-mediated MIF expression and M1 macrophage polarization.

Autophagy can function as a survival mechanism for cancer cells and therefore, its inhibition is currently being explored as a therapy for different cancer types. For breast cancer, triple negative breast cancer (TNBC) is the subtype most sensitive to the inhibition of autophagy; but its inhibition has also been shown to promote ROS-dependent secretion of macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine. In this work, we explore the role of MIF in breast cancer, the mechanism by which autophagy inhibition promotes MIF secretion and its effects on neighboring cancer cell signaling and macrophage polarization. We analyzed MIF mRNA expression levels in tumors from breast cancer patients from different subtypes and found that Luminal B, HER2 and Basal subtypes, which are associated to high proliferation, displayed high MIF levels. However, MIF expression had no prognostic relevance in any breast cancer subtype. In addition, we found that autophagy inhibition in 66cl4 TNBC cells increased intracellular Reactive Oxygen Species (ROS) levels, which increased MIF expression and secretion. MIF secreted from 66cl4 TNBC cells induced the activation of MIF-regulated pathways in syngeneic cell lines, increasing Akt phosphorylation in 4T1 cells and ERK phosphorylation in 67NR cells. Regarding MIF/ chemokine receptors, higher levels of CD74 and CXCR2 were found in TNBC tumor cell lines when compared to non-tumorigenic cells and CXCR7 was elevated in the highly metastatic 4T1 cell line. Finally, secreted MIF from autophagy deficient 66cl4 cells induced macrophage polarization towards the M1 subtype. Together, our results indicate an important role for the inhibition of autophagy in the regulation of ROS-mediated MIF gene expression and secretion, with paracrine effects on cancer cell signaling and pro-inflammatory repercussions in macrophage M1 polarization. This data should be considered when considering the inhibition of autophagy as a therapy for different types of cancer.

Mediterranean Diet to Prevent the Development of Colon Diseases: A Meta-Analysis of Gut Microbiota Studies.

Gut microbiota dysbiosis is a common feature in colorectal cancer (CRC) and inflammatory bowel diseases (IBD). Adoption of the Mediterranean diet (MD) has been proposed as a therapeutic approach for the prevention of multiple diseases, and one of its mechanisms of action is the modulation of the microbiota. We aimed to determine whether MD can be used as a preventive measure against cancer and inflammation-related diseases of the gut, based on its capacity to modulate the local microbiota. A joint meta-analysis of publicly available 16S data derived from subjects following MD or other diets and from patients with CRC, IBD, or other gut-related diseases was conducted. We observed that the microbiota associated with MD was enriched in bacteria that promote an anti-inflammatory environment but low in taxa with pro-inflammatory properties capable of altering intestinal barrier functions. We found an opposite trend in patients with intestinal diseases, including cancer. Some of these differences were maintained even when MD was compared to healthy controls without a defined diet. Our findings highlight the unique effects of MD on the gut microbiota and suggest that integrating MD principles into a person's lifestyle may serve as a preventive method against cancer and other gut-related diseases.

Corrigendum to "Macrophage Migration Inhibitory Factor Promotes the Interaction between the Tumor, Macrophages, and T Cells to Regulate the Progression of Chemically Induced Colitis-Associated Colorectal Cancer".

[This corrects the article DOI: 10.1155/2019/2056085.].

Relevance of Regulatory T Cells during Colorectal Cancer Development.

In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called "phenotypic plasticity", where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC.

Immune modulation by the macrophage migration inhibitory factor (MIF) family: D-dopachrome tautomerase (DDT) is not (always) a backup system.

Human macrophage migration inhibition factor (MIF) is a protein with cytokine and chemokine properties that regulates a diverse range of physiological functions related to innate immunity and inflammation. Most research has focused on the role of MIF in different inflammatory diseases. D-dopachrome tautomerase (DDT), a different molecule with structural similarities to MIF, which shares receptors and biological functions, has recently been reported, but little is known about its roles and mechanisms. In this review, we sought to understand the similarities and differences between these molecules by summarizing what is known about their different structures, receptors and mechanisms regulating their expression and biological activities with an emphasis on immunological aspects.

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis.

Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial-mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as ß-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-ß, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.

Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer.

Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy has been shown to be necessary for the survival of cancer cells from the triple negative subtype (TNBC), which has the worst prognosis among breast cancers and currently has limited therapeutic options. Autophagy has also been involved in the regulation of protein secretion and, of importance for this work, the inhibition of autophagy is known to promote the secretion of proinflammatory cytokines from distinct cell types. We found that the inhibition of autophagy in TNBC cell lines induced the secretion of the macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine involved in breast cancer invasion and immunomodulation. MIF secretion was dependent on an increase in reactive oxygen species (ROS) induced by the inhibition of autophagy. Importantly, MIF secreted from autophagy-deficient cells increased the migration of cells not treated with autophagy inhibitors, indicating that autophagy inhibition in cancer cells promoted malignancy in neighboring cells through the release of secreted factors, and that a combinatorial approach should be evaluated for cancer therapy.