HallMarks
What is a "Hallmark" of cancer?
a biological capability that human cells acquire as they develop into tumors
Ecosystems created by resident bacteria and fungi which have a profound impact on health and disease
the microbiomes
How then is the cancer cell genome reprogrammed, other than oncogenic mutations?
The tumor microenvironment can cause broad changes in the epigenome, from which changes beneficial to the phenotypic selection of hallmark capabilities can result in clonal outgrowth of cancer cells with enhanced fitness for proliferative expansion.
Who can tell me the 3 basic mechanisms discussed in this section in regards to how unlocking cellular plasticity results in cancerous behavior?
Dedifferentiation, Blocked Differentiation, and Transdifferentiation
What is a Senescent Cell and what are some examples of characteristics
Cellular senescence is a typically irreversible form of proliferative arrest, likely evolved as a protective mechanism for maintaining tissue homeostasis, ostensibly as a complementary mechanism to programmed cell death that serves to inactivate and in due course remove diseased, dysfunctional, or otherwise unnecessary cells.
What was the intent of developing the Hallmarks of Cancer?
The intent was to provide a conceptual scaffold that would make it possible to rationalize the complex phenotypes of diverse human tumor types and variants in terms of a common set of underlying cellular parameters.
What is dysbiosis?
Distortions in microbial populations
What is one common characteristic of tumors and is a consequence to insufficient vascularization?
What is type of cancer that exhibits this condition?
Hypoxia
Pediatric ependymoma
Lacks recurrent mutations, in particular a dearth of driver mutations in oncogenes and tumor suppressors.
Rather, the aberrant growth of these cancer cells is demonstrably governed by a gene regulatory program induced by hypoxia.
Notably, the putative cell-of-origin of this cancer resides in a hypoxic compartment, likely sensitizing cells resident therein to the initiation of tumorigenesis by as yet unknown cofactors.
Describe the concept of Dedifferentiation and provide an example of a type of cancer that exhibits this mechanism?
A cellular process that causes cells to grow in reverse, from a more differentiated to a less differentiated state.
Colon carcinogenesis, where both differentiated colonic epithelial cells and stem cells have been implicated as cell-of-origin.
What is the The senescence-associated secretory phenotype (SASP)?
In addition to shutting down the cell division cycle, the senescence program evokes changes in cell morphology and metabolism and, most profoundly, the activation of a senescence-associated secretory phenotype (SASP) involving the release of a plethora of bioactive proteins, including chemokines, cytokines, and proteases whose identity is dependent on the cell and tissue type from which a senescent cell arises
Name 2 of the Original Hallmarks
Sustaining Proliferative Signaling
Evading Growth Suppressors
Avoiding Immune Destruction
Enabling Replicative Immortality
Activating Invasion & Metastasis
Inducing or Accessing Vasculature
Resisting Cell Death
Deregulating Cellular Metabolism
How is the Gut microbiome is fundamentally important for the function of the large intestine?
Degrading and importing nutrients into the body as part of metabolic homeostasis
Distortions in the microbial populations—dysbiosis—in the colon can cause a spectrum of physiologic maladies
Among these has been the suspicion that the susceptibility, development, and pathogenesis of colon cancer is influenced by the gut microbiome
•Recent studies have shown there are both cancer-protective and tumor-promoting microbiomes, involving particular bacterial species, which can modulate the incidence and pathogenesis of colon tumors
What is another line of evidence for microenvironmentally mediated epigenetic regulation?
A classic example involves the reversible induction of invasiveness of cancer cells at the margins of many solid tumors, orchestrated by the developmental regulatory program known as the epithelial-to- mesenchymal transition
Describe the concept of Blocked Differentiation and provide an example of a type of cancer that exhibits this mechanism?
•When incompletely differentiated progenitor cells can suffer regulatory changes that actively block their continued advance into fully differentiated, typically non-proliferative states.
•Acute promyelocytic leukemia (APL) results from a chromosomal translocation that fuses the PML locus with the gene encoding the retinoic acid α nuclear receptor (RARα). Myeloid progenitor cells bearing such translocations are evidently unable to continue their usual terminal differentiation into granulocytes, resulting in cells trapped in a proliferative, promyelocytic progenitor stage
What can induce senescence in cells?
What are the two emerging Hallmarks that were later added?
These two enabling processes were genome instability and tumor-promoting inflammation
What are the Two general effects that are established for tumor-promoting microbiomes and in some cases for specific tumor-promoting bacterial species?
•mutagenesis of the colonic epithelium
•Additionally, bacteria have been reported to bind to the surface of colonic epithelial cells and produce ligand mimetics that stimulate epithelial proliferation, contributing in neoplastic cells to the hallmark capability for proliferative signaling
What is Epithelial to mesenchymal transition (EMT)
a cellular process that causes epithelial cells to lose their polarity and cell-to-cell adhesion, and gain invasive and migratory properties
Describe the concept of Transdifferentiation and provide an example of a type of cancer that exhibits this mechanism?
•When cells that were initially committed into one differentiation pathway switch to an entirely different developmental program, thereby acquiring tissue-specific traits that were not preordained by their normal cells-of-origin
Barrett's esophagus-Chronic inflammation of stratified squamous epithelium indices transdifferentiation into a simple columns epithelium.
Describe transitory senescence.
•Another facet to the effects of senescent cells in cancer phenotypes involves transitory, reversible cell states
•senescent cancer cells can escape from their SASP-expressing, nonproliferative condition, and resume cell proliferation and manifestation of the associated capabilities of fully viable oncogenic cell
•Such transitory senescence is most well documented in cases of therapy resistance, representing a form of dormancy that circumvents therapeutic targeting of proliferating cancer cells
Name one of the prospective hallmarks discussed today?
“unlocking phenotypic plasticity,” “nonmutational epigenetic reprogramming,” “polymorphic microbiomes,” and “senescent cells”
What has been observed regarding bacteria and the tumor Biome?
•Bacteria can be detected within solid tumors, an observation that has now been substantiated with sophisticated profiling technologies
•In a survey 7 types of cancers were characterized by distinct microbiomes that was localized in cancer cells and immune cells
•Microbiota have been similarly detected in genetically engineered de novo mouse models of lung and pancreas cancer
•functionally implicating the tumor microbiome as an enabler of tumor-promoting inflammation and malignant progression
•Ex: mouse model fecal transplants
How can paracrine signaling effect epigenetic change?
Paracrine signaling involving soluble factors released into the extracellular milieu by the various cell types populating solid tumors can also contribute to the induction of several morphologically distinct invasive growth programs
What is one caveat when considering the three methodologies of cellular plasticity?
Dedifferentiation and blocked differentiation are likely intertwined, being indistinguishable in many tumor types where the cell-of-origin— differentiated cell or progenitor/stem cell—is either unknown or alternatively involved
What is the behavior of Senescence in cancer-associated fibroblasts?
•Hallmark-promoting capabilities of senescent cells are not limited to senescent cancer cells
•Cancer associated fibroblasts (CAF) in tumors have been shown to undergo senescence, creating senescent CAFs that are demonstrably tumor-promoting by virtue of conveying hallmark capabilities to cancer cells in the Tumor Microenviroment.
•senescent fibroblasts in aging skin have been shown to recruit innate immune cells that are both immunosuppressive of adaptive antitumoral immune responses anchored by CD8 T cells, and stimulatory of skin tumor growth