Abstract The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Recently, it was reported that targeting stromal events could improve ...efficacies of current therapeutics and prevent metastatic spreading. Tumor microenvironment is a “complex network” of different cell types, soluble factors, signaling molecules and extracellular matrix components, which orchestrate the fate of tumor progression. As by definition, cancer stem cells (CSCs) are proposed to be the unique cell type able to maintain tumor mass and survive outside the primary tumor at metastatic sites. Being exposed to environmental stressors, including reactive oxygen species (ROS), CSCs have developed a GSH-dependent antioxidant system to improve ROS defense capability and acquire a malignant phenotype. Nevertheless, tumor progression is dependent on extracellular matrix remodeling, fibroblasts and macrophages activation in response to oxidative stress, as well as epithelial mesenchymal transition (EMT)-inducing signals and endothelial and perivascular cells recruitment. Besides providing a survival advantage by inducing de novo angiogenesis, tumor-associated vessels contribute to successful dissemination by facilitating tumor cells entry into the circulatory system and driving the formation of pre-metastatic niche. In this review, we focus on the synergistic effect of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs) in the successful outgrowth of metastasis, integrating therefore many of the emerging models and theories in the field.
Abstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells ...with metastatic properties in patients affected by obesity remain unexplored.
Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.
Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in ...mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.
Notwithstanding cancer patients benefit from a plethora of therapeutic alternatives, drug resistance remains a critical hurdle. Indeed, the high mortality rate is associated with metastatic disease, ...which is mostly incurable due to the refractoriness of metastatic cells to current treatments. Increasing data demonstrate that tumors contain a small subpopulation of cancer stem cells (CSCs) able to establish primary tumor and metastasis. CSCs are endowed with multiple treatment resistance capabilities comprising a highly efficient DNA damage repair machinery, the activation of survival pathways, enhanced cellular plasticity, immune evasion and the adaptation to a hostile microenvironment. Due to the presence of distinct cell populations within a tumor, cancer research has to face the major challenge of targeting the intra-tumoral as well as inter-tumoral heterogeneity. Thus, targeting molecular drivers operating in CSCs, in combination with standard treatments, may improve cancer patients' outcomes, yielding long-lasting responses. Here, we report a comprehensive overview on the most significant therapeutic advances that have changed the known paradigms of cancer treatment with a particular emphasis on newly developed compounds that selectively affect the CSC population. Specifically, we are focusing on innovative therapeutic approaches including differentiation therapy, anti-angiogenic compounds, immunotherapy and inhibition of epigenetic enzymes and microenvironmental cues.
The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by ...IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44
/CD24
cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies.
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Cancer can be considered an aberrant organ with a hierarchical composition of different cell populations. The tumor microenvironment, including the immune cells and related cytokines, is crucial ...during all the steps of tumor development. In particular, type I and II interferons (IFNs) are involved in a plethora of mechanisms that regulate immune responses in cancer, thus balancing immune escape
immune surveillance. IFNs are involved in both the direct and indirect regulation of cancer cell proliferation and metastatic potential. The mutational background of genes involved in IFNs signaling could serve as a prognostic biomarker and a powerful tool to screen cancer patients eligible for checkpoint blocking therapies. We herewith describe the latest findings regarding the contribution of IFNs in colorectal cancer and melanoma by researching their dual role as either tumor promoter or suppressor, in diverse tumor types, and microenvironmental context. We are reporting the most innovative and promising approaches of IFN-based therapies that have achieved considerable outcomes in clinical oncology practice and explain the possible mechanisms responsible for their failure.
Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic ...regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype.
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. ...Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAF
or NRAS
mutations generate papillary or follicular TC, respectively, whereas addition of TP53
generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs.
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