Biology of Melanoma Ostrowski, Stephen M; Fisher, David E
Hematology/oncology clinics of North America,
02/2021, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Melanoma skin cancer is derived from skin melanocytes and has a high risk of metastatic spread. The era of molecular genetics and next-generation sequencing has uncovered the role of oncogenic ...BRAFV600E mutations in many melanomas, validated the role of ultraviolet-induced DNA mutations in melanoma formation, and uncovered many of the molecular events that occur during melanoma development. Targeted therapies and immunotherapy have dramatically improved outcomes and provided an increased rate of cure for metastatic melanoma. This article reviews the formation of melanoma, the molecular events involved in melanoma growth and metastasis, and the biology underlying resistance to melanoma therapies.
Extracellular signal-regulated kinase (ERK)1/2 signalling mediates communication between growth factor receptors and the cell nucleus and has been linked to several key events in the transformation ...process such as proliferation and invasion. We therefore sought to delineate the degree of phosphorylated ERK1/2 in breast cancer and potential links to upstream receptors such as VEGFR2, ErbB2, downstream targets, such as Ets-2, as well as clinico-pathological parameters, clinical outcome and response to tamoxifen. ERK1/2 phosphorylation was assessed by immunohistochemistry using a phospho-specific ERK1/2 antibody in three breast cancer cohorts including a total of 886 tumours arranged in tissue arrays. Cohort I consisted of 114 patients, cohort II of 248 postmenopausal patients randomized to either 2 years of tamoxifen or no adjuvant treatment and cohort III of 524 patients. Surprisingly, ERK1/2 phosphorylation correlated inversely with tumour size. Phosphorylated ERK1/2 was further associated with the presence of VEGFR2 (cohorts II and III) and the degree of phosphorylated Ets-2, indicating in vivo, a signalling cascade from VEGFR2 via ERK1/2 to Ets-2 phosphorylation. Interestingly, ERK1/2 phosphorylation correlated with better survival in untreated patients independently of lymph-node status and tumour size indicating that ERK1/2 signalling might be associated with a less aggressive phenotype. Finally, patients with oestrogen receptor positive and ERK1/2 phosphorylated tumours also had an impaired tamoxifen response.
A better understanding of the cellular targets of HIV infection in the female genital tract may inform HIV prevention efforts. Proposed correlates of cellular susceptibility include the HIV ...co-receptor CCR5, peripheral homing integrins, and immune activation. We used a CCR5-tropic pseudovirus to quantify HIV entry into unstimulated endocervical CD4(+) T cells collected by cytobrush. Virus entry was threefold higher into cervix-derived CD4(+) T cells than blood, but was strongly correlated between these two compartments. Cervix-derived CD4(+) T cells expressing CD69, α(4)β(7), or α(4)β(1) were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in α(4)β(7)(+) and CD69(+) CD4(+) T cells, and to a lesser extent in α(4)β(1)(+) CD4(+) T cells. Direct binding of gp140 to integrins was not observed, integrin inhibitors had no effect on virus entry, and pseudotypes with an env that preferentially binds α(4)β(7) still demonstrated enhanced entry into α(4)β(1)(+) cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4(+) T cells, and those expressing α(4)β(7) or α(4)β(1). This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of α(4)β(7) or α(4)β(1) with HIV envelope.
Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin ...pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e., “tanning pathway”). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway (“sunless tanning”) represents a potential strategy for skin cancer prevention, particularly in those with light skin or the “red hair” phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway.
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The seasonal cycle of sea surface salinity (SSS) along the Angolan coast is investigated using observations and a regional ocean model. The model reproduces the main characteristic of the seasonal ...cycle of SSS along the Angolan coast, such as the freshwater discharge signature off the Congo River plume and the low‐salinity observed in February/March and October/November along the Angolan coast. The model also reproduces the two maxima of salinity in June/July and December/January. The analysis of the model salt budget reveals that the semi‐annual cycle of SSS is controlled by the meridional advection of surface water, the vertical advection of subsurface water, and the mixing at the base of the mixed layer. The meridional advection is controlled by the Angola Current which brings low‐salinity water from offshore region of the Congolese coast toward the south Angolan coast in February/March and October/November. The vertical advection contribution is modulated by the vertical stratification of salinity and not by vertical velocities which peak during the main Angolan upwelling season. The vertical stratification is due to the low‐salinity intrusion at the Angolan coast that creates a strong vertical salinity gradient with low‐salinity at the surface and high salinity at the subsurface.
Plain Language Summary
Ocean salinity is a key driver of oceanic circulation, and it affects profoundly the marine coastal ecosystem. We study here the seasonal cycle of the upper ocean salinity off the Angolan coast. We observe a low‐salinity water intrusion in February/March and October/November along the Angolan coast. We find the low‐salinity intrusion due to the well‐known Angola Current that brings low‐salinity waters from the Congo River plume southward. On its way south along the Angola coast, surface water gains salt from subsurface water that rises to the surface through upwelling and mixing at the base of the ocean surface mixed layer.
Key Points
The surface salinity along the Angolan coast presents a semi‐annual cycle
The Angola Current drives the low‐salinity intrusion at the Angolan coast while subsurface processes bring salty water toward the surface
The low‐salinity intrusion at the Angolan coast creates a strong vertical salinity gradient that favors vertical salt advection
Prochlorococcus and Synechococcus are major prokaryotic primary producers in the oligotrophic oceans that may be affected by the climate-related increases in nitrogen fixation and subsequent ...phosphorus (P) limitation in some parts of the oceans. Evidence that Prochlorococcus populations in the North Pacific subtropical gyre (NPSG) have increased over the past decades, possibly due to having a competitive advantage under conditions of P limitation, suggests aspects of their P physiology that are important for dictating their in situ success. Here, we compared the physiology of P acquisition and response to P stress (indicated by alkaline phosphatase activity, APA) among isolates of Prochlorococcus and Synechococcus representing different genotypic clades within the marine picophytoplankton lineage (sensu Urbach et al. 1998: J Mol Evol 46:188-201). The 2 Synechococcus isolates examined (WH 8102 and WH 7803) can utilize a wide variety of organic P sources. Of the 3 Prochlorococcus isolates examined, only the HLI genotype, MED4, is capable of growth on a variety of organic P sources. Under conditions of P starvation the 2 Synechococcus strains and Prochlorococcus MED4 exhibit significant increases in APA, above their measurable constitutive activities. The genomes of the Synechococcus strains and Prochlorococcus MED4 indicate the presence of many P-uptake and -regulatory genes required under conditions of P stress, including the phoA gene that encodes for an alkaline phosphatase enzyme. The other isolates of Prochlorococcus, HLII MIT 9312 and LLIV MIT 9313, have distinctly different P-stress responses. MIT 9312, which contains the same P-uptake and -regulatory genes as MED4, except for psip1 and ptrA, has no constitutive APA, but does exhibit measurable, albeit very low, activity when P starved. MIT 9313, which lacks phoA and a functional phosphate-sensing histidine kinase gene, phoR, exhibits low constitutive activity that decreases when the cells become P-starved. These results show variability in P utilization and in P-stress response between the 2 genera of marine unicellular cyanobacteria, and marked differences among Prochlorococcus genotypes, implying that only certain eco/genotypes of these marine cyanobacteria will have an ecological advantage under conditions of P limitation in the oceans. This further points to the critical need to continue developing genotypic- or cell-specific tools to assess the response of the picophytoplankton community to large-scale changes in nutrient conditions in the oceans.
Generalised additive models (GAMs) were applied to survey data to assess the influence of dissolved oxygen, water temperature and year of sampling upon the presence/absence of small (≤15 cm TL), ...medium (16-34 cm TL) and large (≥35 cm TL) size classes of deepwater Cape hake Merluccius paradoxus captured off the west coast of South Africa. Data were obtained from surveys using the RV Dr Fridtjof Nansen conducted in 2003 and from 2005 to 2013 during summer (January-February). Among the variables investigated, oxygen was the most important for the small size class (juveniles), with both low and high constraints (two-sided, 'just right' option), whereas for the medium and large size classes the oxygen effects were one-sided (avoiding lows). This finding, in combination with other published information, suggests that the Orange Banks is a nursery ground for juvenile M. paradoxus and that the area covered by this nursery ground can vary with the optimal oxygen concentration. The temperature constraint was generally wider and weaker than that for oxygen, being two-sided for the small and medium hake and one-sided (avoiding highs) for the large hake. The medium hake displayed the greatest tolerance to the investigated variables, which resulted in the widest distribution for this size class. Temperature, oxygen and sampling year play an important role in determining the distribution of M. paradoxus, but details of the biology (life cycle) of the species, such as its pelagic-demersal transition and associated movements, are no less important.
Purpose
High expression of glioma-associated oncogene homolog-1 (GLI1) is associated with poor prognosis in estrogen receptor (ER) positive breast cancers. We sought to define a GLI1-dependent gene ...signature in ER-positive tumors that could further stratify patients at higher risk for disease recurrence and potentially lead to novel combination therapies.
Methods
We identified an inverse correlation between
GLI1
expression and distant disease-free survival (DFS) using a dataset developed at MD Anderson Cancer Center (Hatzis dataset) containing clinical data from 508 breast cancer patients. Using a qPCR-based microarray platform, we identified genes differentially regulated by GLI1 in MCF7 cells and then determined if expression of these genes correlated with
GLI1
expression in patient tumor samples. Statistical comparison between the groups was performed by ANOVA. Direct comparison of two groups was done by a two-tailed
t
test. Correlations between variables were done by Pearson’s method.
Results
Expression of
GLI1
and its target genes correlated significantly with worse distant DFS in breast cancer patients with Luminal A molecular subtype. Particularly, co-expression of
GLI1
with
EGFR
and/or
SNAI1
, two of the identified GLI1 targets, was predictive of worse distant DFS in this subtype. Furthermore, patients with Luminal A tumors with a high GLI1 signature had a shorter distant DFS compared to the Luminal B subtype and the outcome for this group was comparable to patients with HER2-positive or basal-like tumors.
Conclusion
We have identified a novel
GLI1
gene signature that is associated with worse clinical outcomes among the patients with Luminal A subtype of breast cancer.
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