Apoptotic cells may drive cell death in hair follicles during their regression cycle.

Intravital microscopy in live mice has shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-ß (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays essential role in death induction. Because the DP cells are not necessary for completion of the cycle but only for its initiation it is still an open question what is the mechanism leading to the propagation of apoptosis towards the regenerative stem cell population. Here, we use a quantitative analysis of the length of hair follicles during their regression cycle. The data are consistent with a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. The observation that the apoptosis slows down as the apoptotic front approaches the stem cells at the end of the follicle is consistent with a gradient of a pro-survival signal sent by these stem cells. An experiment that can falsify this mechanism is proposed.

Drug resistant cells with very large proliferative potential grow exponentially in metastatic prostate cancer.

Most metastatic cancers develop drug resistance during treatment and continue to grow, driven by a subpopulation of cancer cells unresponsive to the therapy being administered. There is evidence that metastases are formed by phenotypically plastic cancer cells with stem-cell like properties. Currently the population structure and growth dynamics of the resulting metastatic tumors is unknown. Here, using scaling analysis of clinical data of tumor burden in patients with metastatic prostate cancer, we show that the drug resistant, metastasis-causing cells (MCC) are capable of producing drug resistant, exponentially growing tumors, responsible for tumor growth as a patient receives different treatments.

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA. Additionally we estimated mathematically the caloric burden of such tumors using data on mitotic and apoptotic indices. We conclude outgrowth of cells harboring intrinsic or acquired MT-KRAS cannot explain resistance to anti-EGFR (epidermal growth factor receptor) antibodies. Rates of tumor growth with panitumumab are unaffected by presence/absence of MT-KRAS. While MT-KRAS cells may be resistant to anti-EGFR antibodies, WT-KRAS cells also rapidly bypass this blockade suggesting inherent resistance mechanisms are responsible and a neutral evolution model is most appropriate. Using the above clinical data on tumor doubling times and mitotic and apoptotic indices we estimated the caloric intake required to support tumor growth and suggest it may explain in part cancer-associated cachexia.

Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool.

Tissue homeostasis is achieved through a balance of cell production (growth) and elimination (regression). In contrast to tissue growth, the cells and molecular signals required for tissue regression remain unknown. To investigate physiological tissue regression, we use the mouse hair follicle, which cycles stereotypically between phases of growth and regression while maintaining a pool of stem cells to perpetuate tissue regeneration. Here we show by intravital microscopy in live mice that the regression phase eliminates the majority of the epithelial cells by two distinct mechanisms: terminal differentiation of suprabasal cells and a spatial gradient of apoptosis of basal cells. Furthermore, we demonstrate that basal epithelial cells collectively act as phagocytes to clear dying epithelial neighbours. Through cellular and genetic ablation we show that epithelial cell death is extrinsically induced through transforming growth factor (TGF)-ß activation and mesenchymal crosstalk. Strikingly, our data show that regression acts to reduce the stem cell pool, as inhibition of regression results in excess basal epithelial cells with regenerative abilities. This study identifies the cellular behaviours and molecular mechanisms of regression that counterbalance growth to maintain tissue homeostasis.

Therapies with diverse mechanisms of action kill cells by a similar exponential process in advanced cancers.

Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor. Here, we examine theoretically different models of cell killing and analyze data from clinical trials based on these models. We show that the best description of clinical outcomes is by first-order kinetics with exponential decrease of tumor quantity. We analyzed the total tumor quantity in a diverse group of clinical trials with various cancers during the administration of different classes of anticancer agents and in all cases observed that the models that best fit the data describe the decrease of the sensitive tumor fraction exponentially. The exponential decrease suggests that all drug-sensitive cancer cells have a single rate-limiting step on the path to cell death. If there are intermediate steps in the path to cell death, they are not rate limiting in the observational time scale utilized in clinical trials--tumor restaging at 6- to 8-week intervals. On shorter time scales, there might be intermediate steps, but the rate-limiting step is the same. Our analysis, thus, points to a common pathway to cell death for cancer cells in patients. See all articles in this Cancer Research section, "Physics in Cancer Research."

Scientific priorities for the BRAIN Initiative.

We present a summary of the scientific deliberations and major conclusions that arose from a workshop on the BRAIN Initiative.

Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma.

Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents.

Hazard ratios in cancer clinical trials--a primer.

The increase and diversity of clinical trial data has resulted in a greater reliance on statistical analyses to discern value. Assessing differences between two similar survival curves can pose a challenge for those without formal training in statistical interpretation; therefore, there has been an increased reliance on hazard ratios often to the exclusion of more-traditional survival measures. However, because a hazard ratio lacks dimensions it can only inform the reader about the reliability and uniformity of the data. It does not provide practitioners with quantitative values they can use, nor does it provide information they can discuss with patients. Motivated by a non-scientific poll of oncologists in training and those with board certification that suggested only a limited understanding of the derivation of hazard ratios we undertook this presentation of hazard ratios: a measure of treatment efficacy that is increasingly used and often misused.

Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche.

Telomere loss at each cell replication limits the proliferative capacity of normal cells, including adult stem cells. Entering replicative senescence protects dividing cells from neoplastic transformation, but also contributes to aging of the tissue. Recent experiments have shown that intestinal mouse stem cells divide symmetrically, at random make decisions to remain stem cells or to differentiate, and gradually lose telomeric DNA. A cell's decision whether to differentiate or to remain a stem cell depends on the local cellular and chemical environment and thus tissue architecture is expected to play role in cell proliferation dynamics. To take into account the structure of the stem cell niche in determining its proliferative potential and susceptibility to cancer, a theoretical model is introduced and the niche proliferative potential is quantified for different architectures. The niche proliferative potential is quantitatively related to the proliferative potential of the individual stem cells for different structural classes of the stem cell niche. Stem cells at the periphery of a niche are under pressure to divide and to differentiate, as well as to maintain the stem cell niche boundary, and thus the geometry of the stem cell niche is expected to play a role in determining the stem cell division sequence and differentiation. Smaller surface-to-volume ratio is associated with higher susceptibility to cancer, higher tissue renewal capacity, and decreased aging rate. Several testable experimental predictions are discussed, as well the presence of stochastic effects.

Telomere sister chromatid exchange and the process of aging.

Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence. Additionally high T-SCE rates have been observed in cells with deficiencies in WRN and BLM, the genes that are defective in Werner's and Bloom's syndromes, implying a connection to premature aging. In this Research Perspective we will explore some of the implications this recent work has for human health.

Hyper telomere recombination accelerates replicative senescence and may promote premature aging.

Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE-but not G-SCE-frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.

Biophysical modeling of phase changes in BOLD fMRI.

In BOLD fMRI, stimulus related phase changes have been repeatedly observed in humans. However, virtually all fMRI processing utilizes the magnitude information only, while ignoring the phase. This results in an unnecessary loss of physiological information and signal-to-noise efficiency. A widely held view is that the BOLD phase change is zero for a voxel containing randomly orientated blood vessels and that phase changes are only due to the presence of large vessels. Based on a previously developed theoretical model, we show through simulations and experimental human BOLD fMRI data that a non-zero phase change can be present in a region with randomly oriented vessels. Using simulations of the model, we first demonstrate that a spatially distributed susceptibility results in a non-zero phase distribution. Next, experimental data in a finger-tapping experiment show consistent bipolar phase distribution across multiple subjects. This model is then used to show that in theory a bipolar phase distribution can also be produced by the model. Finally, we show that the model can produce a bipolar phase pattern consistent with that observed in the experimental data. Understanding of the mechanisms behind the experimentally observed phase changes in BOLD fMRI would be an important step forward and will enable biophysical model based methods for integrating the phase and magnitude information in BOLD fMRI experiments.

Cell proliferation in the presence of telomerase.

BACKGROUND: Telomerase, which is active early in development and later in stem and germline cells, is also active in the majority of human cancers. One of the known functions of telomerase is to extend the ends of linear chromosomes, countering their gradual shortening at each cell division due to the end replication problem and postreplication processing. Telomerase concentration levels vary between different cell types as well as between different tumors. In addition variable telomerase concentrations will exist in different cells in the same tumor when telomerase inhibitors are used, because of limitations of drug delivery in tissue. Telomerase extends short telomeres more frequently than long telomeres and the relation between the extension frequency and the telomere length is nonlinear. METHODOLOGY/PRINCIPAL FINDINGS: Here, the biological data of the nonlinear telomerase-telomere dynamics is incorporated in a mathematical theory to relate the proliferative potential of a cell to the telomerase concentration in that cell. The main result of the paper is that the proliferative capacity of a cell grows exponentially with the telomerase concentration. CONCLUSIONS/SIGNIFICANCE: The theory presented here suggests that long term telomerase inhibition in every cancer progenitor or cancer stem cell is needed for successful telomere targeted cancer treatment. This theory also can be used to plan and assess the results of clinical trials targeting telomerase.

Versatile protection from mutagenic DNA lesions conferred by bipartite recognition in nucleotide excision repair.

Nucleotide excision repair is a cut-and-patch pathway that eliminates potentially mutagenic DNA lesions caused by ultraviolet light, electrophilic chemicals, oxygen radicals and many other genetic insults. Unlike antigen recognition by the immune system, which employs billions of immunoglobulins and T-cell receptors, the nucleotide excision repair complex relies on just a few generic factors to detect an extremely wide range of DNA adducts. This molecular versatility is achieved by a bipartite strategy initiated by the detection of abnormal strand fluctuations, followed by the localization of injured residues through an enzymatic scanning process coupled to DNA unwinding. The early recognition subunits are able to probe the thermodynamic properties of nucleic acid substrates but avoid direct contacts with chemically altered bases. Only downstream subunits of the bipartite recognition process interact more closely with damaged bases to delineate the sites of DNA incision. Thus, consecutive factors expand the spectrum of deleterious genetic lesions conveyed to DNA repair by detecting distinct molecular features of target substrates.

Telomere exchange and asymmetric segregation of chromosomes can account for the unlimited proliferative potential of ALT cell populations.

Telomerase-negative cancer cells show increased telomere sister chromatid exchange (T-SCE) rates, a phenomenon that has been associated with an alternative lengthening of telomeres (ALT) mechanism for maintaining telomeres in this subset of cancers. Here we examine whether or not T-SCE can maintain telomeres in human cells using a combinatorial model capable of describing how telomere lengths evolve over time. Our results show that random T-SCE is unlikely to be the mechanism of telomere maintenance of ALT human cells, but that increased T-SCE rates combined with a recently proposed novel mechanism of non-random segregation of chromosomes with long telomeres preferentially into the same daughter cell during cell division can stabilize chromosome ends in ALT cancers. At the end we discuss a possible experiment that can validate the findings of this study.

DNA repair triggered by sensors of helical dynamics.

Nucleotide excision repair is a constitutive stress response that eliminates DNA lesions induced by multiple genotoxic agents. Unlike the immune system, which generates billions of immunoglobulins and T cell receptors for antigen recognition, the nucleotide excision repair complex uses only a few generic factors to detect an astounding diversity of DNA modifications. New data favor an unexpected strategy whereby damage recognition is initiated by the detection of abnormal oscillations in the undamaged strand opposite to DNA lesions. Another core subunit recognizes the increased susceptibility of DNA to be kinked at injured sites. We suggest that early nucleotide excision repair factors gain substrate versatility by avoiding direct contacts with modified residues and exploiting instead the altered dynamics of damaged DNA duplexes.

Acoustic attenuation probe for Fermion superfluidity in ultracold-atom gases.

Dilute gas Bose-Einstein condensates (BEC's), currently used to cool fermionic atoms in atom traps, can also probe the superfluidity of these fermions. The damping rate of BEC-acoustic excitations (phonon modes), measured in the middle of the trap as a function of the phonon momentum, yields an unambiguous signature of BCS-like superfluidity, provides a measurement of the superfluid gap parameter, and gives an estimate of the size of the Cooper pairs in the BEC-BCS crossover regime. We also predict kinks in the momentum dependence of the damping rate which can reveal detailed information about the fermion quasiparticle dispersion relation.

Density and spin response functions in ultracold fermionic atom gases.

We propose a new method of detecting the onset of superfluidity in a two-component ultracold fermionic gas of atoms governed by an attractive short-range interaction. By studying the two-body correlation functions we find that a measurement of the momentum distribution of the density and spin-response functions allows one to access separately the normal and anomalous densities. The change in sign at low momentum transfer of the normal-ordered part of the density response function signals the transition between a BEC and a BCS regime, characterized by small and large pairs, respectively. This change in sign of the density response function represents an unambiguous signature of the BEC-to-BCS crossover. Spin rotational symmetry breaking due to the magnetic field, if observed, can be used to validate the one-channel model.