Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific ...expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Malignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is ...frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating β-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and Braf
V600E mutation, we demonstrate that β-catenin is a central mediator of melanoma metastasis to the lymph nodes and lungs. In addition to altering metastasis, β-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with β-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma.
► β- catenin loss in Pten/Braf melanomas improves survival and inhibits metastasis ► β-catenin stabilization in Pten/Braf melanomas enhances metastasis ► Highly differentiated melanomas can be very metastatic in vivo ► β-catenin status in melanoma regulates PI3K/Akt and MAPK/Erk signaling
Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the ...accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Opinion statement
Cutaneous T cell lymphomas (CTCLs) are non-Hodgkin lymphomas of skin homing T cells. Although early-stage disease may be limited to the skin, tumor cells in later stage disease can ...populate the blood, the lymph nodes, and the visceral organs. Unfortunately, there are few molecular biomarkers to guide diagnosis, staging, or treatment of CTCL. Diagnosis of CTCL can be challenging and requires the synthesis of clinical findings, histopathology, and T cell clonality studies; however, none of these tests are entirely sensitive or specific for CTCL. Treatment of CTCL is often empiric and is not typically based on specific molecular alterations, as is common in other cancers. In part, limitations in diagnosis and treatment selection reflect the limited insight into the genetic basis of CTCL. Recent next-generation sequencing has revolutionized our understanding of the mutational landscape in this disease. These analyses have uncovered ultraviolet radiation and recombination activating gene (RAG) endonucleases as important mutagens. Furthermore, these studies have revealed potentially targetable oncogenic mutations in the T cell receptor complex, NF-κB, and JAK-STAT signaling pathways. Collectively, these somatic mutations drive lymphomagenesis via cancer-promoting changes in proliferation, apoptosis, and T cell effector function. We expect that these genetic findings will launch a new era of precision medicine in CTCL.
Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer ...models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.
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•Hyperinsulinemia in HFD mice increases glucose uptake and oxidation in tumors•Metformin and CRMP slow colon tumors in two mouse models by reversing hyperinsulinemia•Reducing tumor glucose oxidation may slow obesity-associated cancers
Wang et al. demonstrate that diet-induced hyperinsulinemia increases colon adenocarcinoma tumor glucose uptake and oxidation in mice. They further demonstrate that reversal of hyperinsulinemia by a liver-specific mitochondrial protonophore is sufficient to reverse the obesity-induced acceleration of tumor growth.
Fever, Hypotension, and a Worsening Necrotic Wound Peterson, Danielle M; Damsky, William E; Vesely, Matthew D
JAMA : the journal of the American Medical Association,
04/2022, Letnik:
327, Številka:
15
Journal Article
Recenzirano
On the day of giving birth via a normal vaginal delivery, a healthy woman in her 20s developed painful swelling on her right thigh, at the site of a methergine injection administered 1 day prior. ...Despite 3 days of treatment with an oral antibiotic (cefalexin), her thigh pain and swelling did not improve, and she was readmitted to the hospital and intravenous clindamycin was started. Wound cultures and blood cultures obtained during incision and drainage performed on hospital day 1 were negative for bacterial, mycobacterial, and fungal organisms. The following day, her temperature was 39.4 degrees C, blood pressure was 86/42 mm Hg, and heart rate was 131/min. She was transferred to the intensive care unit for presumed septic shock, and her antibiotics were changed to vancomycin and meropenem. Surgical debridement of the right thigh was performed on hospital day 3.
The peripheral T cell repertoire of healthy individuals contains self-reactive T cells
. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or ...anergy of self-reactive CD8 T cells
. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors
. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.
Decoding melanoma metastasis Damsky, William E; Rosenbaum, Lara E; Bosenberg, Marcus
Cancers,
12/2010, Letnik:
3, Številka:
1
Journal Article, Book Review
Recenzirano
Odprti dostop
Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma. Evidence suggests melanoma has a predilection for metastasis to particular organs. Experimental analyses ...have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these analyses are complicated by observations of metastatic dormancy and dissemination of melanocytes that are not yet fully malignant. Additionally, tumor extrinsic factors in the microenvironment, both at the site of the primary tumor and the site of metastasis, play important roles in mediating the metastatic process. As metastasis research moves forward, paradigms explaining melanoma metastasis as a step-wise process must also reflect the temporal complexity and heterogeneity in progression of this disease. Genetic drivers of melanoma as well as extrinsic regulators of disease spread, particularly those that mediate metastasis to specific organs, must also be incorporated into newer models of melanoma metastasis.
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