Epigenetics is no longer something to observe, but is now something to seek to modify for therapeutic purposes. Study targeted CPG islands for hypermethylation in primary breast cancer cells to arrest cell cycle and stop senescence escape.
Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
Reverse Warburg Effect
secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
oxidative stress has an important role in the initiation and preservation of breast cancer progression
cancer preventive role of healthy mitochondria
the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
However, diets rich in antioxidants have fallen short in sufficiently preventing cancer
hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.
age-progressive loss of telomere function in mice has been shown to provoke widespread p53 activation resulting in activation of cellular checkpoints of apoptosis, impaired proliferation and senescence, compromised tissue stem cell and progenitor function, marked tissue atrophy and physiological impairment in many organ systems
Despite chromosomal instability, the brief course of telomerase reactivation was not sufficient to promote carcinogenesis (data not shown), a finding consistent with a role for telomerase in promoting progression of established neoplasms
The anti-aging role of telomerase has been demonstrated to be largely mediated by its canonical role in elongating telomeres, which prevents the accumulation of critically short telomeres and loss of tissue homeostasis
Short telomeres, and subsequent DDR activation, could occur both in cancer and aging
increased abundance of short telomeres correlates with higher genomic instability and decreased longevity in various organisms, including mice, zebrafish, and yeast
mice deficient for telomerase or for telomere binding proteins are characterized by accelerated age-related defects
In humans, short telomeres are considered good indicators of an individual’s health status and correlate with both genetic and environmental factors
Although recent findings strongly support the idea that short telomeres drive several age-related diseases 38 we cannot exclude the possibility that in some situations short telomeres may be a consequence of the disease itself.
the current view is that telomerase deficiency may contribute to the early steps of cancer development by fueling chromosomal instability, while subsequent activation of telomerase may be necessary to allow tumor growth and tumor progression towards more malignant states
telomerase activation can be an early event in cancer, it is not necessary for cancer initiation
telomerase can stimulate tumor progression by ensuring maintenance of telomeres above a critically short length, thus preventing induction of cellular senescence or apoptosis
Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells
recent evidence demonstrated that short telomeres alone could lead to genomic instability and cancer
Getting rid of telomerase can also be problematic; the lack of telomerase could lead to increased chromosomal instability, which in turn could be at the basis for cancer initiation when tumor suppressor barriers are bypassed
telomerase activation is a potential therapeutic strategy for the treatment of age-related diseases
telomerase activation in adult or old mice by means of a gene therapy strategy was shown to be sufficient to improve metabolic fitness, neuromuscular capacity, and prevent bone loss, as well as significantly increase both median and maximum longevity, without increased cancer incidence
These studies suggest that telomerase expression could be considered a feasible approach to reverse tissue dysfunction and extend healthy lifespan without increasing cancer incidence
humans almost completely lose telomerase activity from somatic tissues in the adulthood
a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging
Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor
Telomerase activity and longer telomere length is shown to correlated inversely with many chronic diseases of aging. In contrast, telomerase activity is found to be involved in carcinogenesis. Increased carcinogenic potential of telomerase activity has not borne out in studies. In addition, increased CD8 cell activity as a result of telomerase activation will actually decrease carcinogenic potential via NK activation.