Apoptosis drives cancer cells proliferate and metastasize.

Cancer has been considered to be the result of accumulated gene mutations, which result in uncontrolled cell proliferations for a long time. Cancers are also regarded to be capable of immune evasion. Furthermore, resistance to apoptosis was recognized as an important trait of cancer in the last score of years. However, there are numerous paradoxical issues in this whole set of theory. For example, there is no known set of genes of which mutations are responsible for human cancers. As for the trait of 'resistance to apoptosis', the fact is that cancer has increased frequency of apoptosis. The more malignant the tumour is, the more apoptosis shows. In this study, we propose a new theory that apoptosis plays a key role in the malignant progression and metastasis of cancer. The growth of tumour is the difference between tumour cell proliferation and attrition plus the hyperplastic growth of stroma. Increased and unpreventable death caused by innate or environmental factors such as ischaemia and inflammation drives the tumour cells to proliferate relentlessly, move to new lands to establish colonies. In short, increased cell death is the origin of malignancy.

Invasive cancers are not necessarily from preformed in situ tumours - an alternative way of carcinogenesis from misplaced stem cells.

Cancers are thought to be the result of accumulated gene mutations in cells. Carcinomas, which are cancers arising from epithelial tissues usually go through several stages of development: atypical hyperplasia, carcinoma in situ and then invasive carcinoma, which might further metastasize. However, we think that the present pathological data are enough to prove that there might be an alternative way of carcinogenesis. We propose that majority of invasive cancers arise in the connective tissue stroma de novo, from the misplaced epithelial stem cells which come to the wrong land of connective tissue stroma by accident. The in situ carcinomas, which are mostly curable, should not be considered genuine cancer, but rather as quasi-cancer. We design this new theory of carcinogenesis as the stem cell misplacement theory (SCMT). Our SCMT theory chains together other carcinogenesis theories such as the inflammation-cancer chain, the stem cell theory and the tissue organization field theory. However, we deny the pathway of somatic mutation theory as the major pathway of carcinogenesis.

Life history tradeoffs in humans: increased life expectancy with sperm count reduction.

Although not without controversy, as a general trend, the human sperm count is declining world-wide. One major reason for such a decline is an increase in the human life-span.  According to the life history tradeoff theory, fecundity is inversely related to the lifespan; the longer the lifespan, the lower the fecundity. This is essential to the maintainance of diversity and balance of different species. Such a corrleation validated by experimental data that show that the extension of life in Caenorhabditis elegans, Drosophila and Rodents is  associated with reduction in fecundity. The demographic data from a public data source, shows that the total fertility rate is positively correlated with the infant death rate, it is inversely correlated with the life expectancy. We postulate that the fall in spermatogenesis might be regulated by the neuroendocrine system that underlie human longevity.

Genetic instability in bladder cancer assessed by the comet assay.

BACKGROUND: Latent genetic instability has been associated with an increased risk for several cancers. We used the comet assay (single-cell gel electrophoresis) to assess whether genetic instability, as reflected by susceptibility to DNA damage, was associated with the risk of bladder cancer in a case-control study. METHODS: We used the comet assay to measure baseline and benzo[a]pyrene diol epoxide (BPDE)- and gamma-radiation-induced DNA damage in individual peripheral blood lymphocytes from 114 incident case patients with bladder cancer and 145 matched healthy control subjects. All subjects provided personal information, including smoking history. DNA damage was visualized with the comet assay and quantified by the Olive tail moment parameter, a relative measure. Multivariable analysis was used to assess relative risks for bladder cancer associated with DNA damage. All statistical tests were two-sided. RESULTS: Baseline levels of DNA damage were statistically significantly higher in case patients (tail moment = 1.40) than in control subjects (tail moment = 1.21) (difference = 0.19, 95% confidence interval [CI] = 0.04 to 0.32; P =.015), as were gamma-radiation-induced (tail moment = 4.76 versus 4.22; difference = 0.54, 95% CI = 0.11 to 0.96; P =.013) and BPDE-induced (tail moment = 4.06 versus 3.45; difference = 0.61, 95% CI = 0.23 to 0.99; P =.002) DNA damage. When data were dichotomized at the median value for DNA damage in control subjects and adjusted for age, sex, ethnicity, and smoking status, an increased estimated relative risk of bladder cancer was statistically significantly associated with DNA damage at baseline (odds ratio [OR] = 1.84, 95% CI = 1.07 to 3.15) and after gamma-radiation (OR = 1.81, 95% CI = 1.04 to 3.14) but not after BPDE treatment (OR = 1.69, 95% CI = 0.98 to 2.93). CONCLUSION: Latent genetic instability as measured by the comet assay is associated with an increased estimated relative risk of bladder cancer.

Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer.

The deregulated expression of cyclin E as measured by the overexpression of its low molecular weight (LMW) isoforms is a powerful predictor of poor outcome in patients with breast cancer. The mechanism by which these LMW forms give tumor cells a growth advantage is not known and is the subject of this article. In this article, we provide the pathobiological mechanisms of how these LMW forms are involved in disease progression. Specifically, we show that overexpression of the LMW forms of cyclin E but not the full-length form in MCF-7 results in (a) their hyperactivity because of increased affinity for cdk2 and resistance to inhibition by the cyclin-dependent kinase inhibitors p21 and p27, (b) resistance to the growth inhibiting effects of antiestrogens, and (c) chromosomal instability. Lastly, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. Collectively, the biochemical and functional differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. These properties of the LMW forms cyclin E suggest that they are not just surrogate markers of poor outcome but bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.