Understanding the Bone in Cancer Metastasis Fornetti, Jaime; Welm, Alana L; Stewart, Sheila A
Journal of bone and mineral research,
December 2018, Letnik:
33, Številka:
12
Journal Article
Cellular senescence plays a critical role in tumorigenesis. Once thought of as a tissue culture artefact by some researchers, senescence is now a major field of study. Although there are common ...molecular mechanisms that enforce the growth arrest that characterizes the phenotype, the impact of senescence is varied and can, in some instances, have opposite effects on tumorigenesis. It has become clearer that the cell of origin and the tissue in question dictate the impact of senescence on tumorigenesis. In this Review, we unravel this complexity by focusing on how senescence impacts tumorigenesis when it arises within incipient tumour cells versus stromal cells, and how these roles can change in different stages of disease progression. In addition, we highlight the diversity of the senescent phenotype and its functional output beyond growth arrest: the senescence-associated secretory phenotype (SASP). Fortunately, a number of new genetic and pharmacologic tools have been developed that are now allowing the senescence phenotype to be parsed further.
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells ...influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.
Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and ...antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.
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•scRNA/CITE-seq and scATAC-seq reveal hallmarks of immune aging in mice and humans•Clonal exhausted-like GZMK+CD8+ T cells accumulate in tissues due to old environment•GZMK secreted by activated GZMK+CD8+ T cells can promote SASP from senescent cells•GZMK+CD8+ Taa rather than GZMB+CD8+ Tem accumulate in human blood with age
Aging affects the immune system and establishes a chronic low-grade inflammation (inflammaging). Mogilenko et al. defined organ-specific and common alterations of immune cell populations in aging and identified a distinct subset of clonal GZMK+ CD8+ T cells as a conserved cellular hallmark of inflammaging in mice and humans.
Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term ...comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.
Tumor-stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid ...cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15(+) myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs.
Breast cancer can recur months to decades after an initial diagnosis and treatment. The mechanisms that control tumor cell dormancy remain poorly understood, making it difficult to predict which ...patients will recur and thus benefit from more rigorous screening and treatments. Unfortunately, the extreme rarity of dormant DTCs has been a major obstacle to their study.
To overcome this challenge, we developed an efficient system to isolate and study rare dormant breast cancer cells from metastatic organs including bones, which represent a major site of metastasis. After isolation of cells from the long bones, we used single cell RNA-sequencing (scRNA-seq) to profile proliferative and dormant PyMT-Bo1 breast cancer cells. We also compared this signature to dormant versus proliferative tumor cells isolated from the lungs. Finally, we compared our dormant signature to human datasets.
We identified a group of genes including Cfh, Gas6, Mme and Ogn that were highly expressed in dormant breast cancer cells present in the bone and lung. Expression of these genes had no impact on dormancy in murine models, but their expression correlated with disease-free survival in primary human breast cancer tumors, suggesting that these genes have predictive value in determining which patients are likely to recur.
Dormant breast cancer cells exhibit a distinct gene expression signature regardless of metastatic site. Genes enriched in dormant breast cancer cells correlate with recurrence-free survival in breast cancer patients.
Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete protumorigenic factors collectively referred to as the senescence-associated ...secretory phenotype (SASP). Here, we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members interleukin (IL)-6 and IL-8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-κB activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of HDAC inhibition, IL-6 and IL-8 expression remained dependent upon ATM and NF-κB, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 inhibition was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer.
More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that ...tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.
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•Stromal changes in the bone drive tumor cell seeding and growth•IL-6-expressing stromal cells are present in human bone•Senescent osteoblasts drive increased osteoclastogenesis and tumor cell seeding•Senescent-derived IL-6 drives localized osteoclastogenesis and tumor cell growth
Luo et al. show that stromal-derived changes are sufficient to increase tumor cell colonization and metastatic growth in the bone. They report that senescent osteoblasts, and, in particular, the senescence-associated secretory phenotype factor IL-6 drives localized osteoclastogenesis and tumor cell growth.
Telomeres: cancer to human aging Stewart, Sheila A; Weinberg, Robert A
Annual review of cell and developmental biology,
01/2006, Letnik:
22
Journal Article
Recenzirano
The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of ...tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.
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