Poly‐aneuploid cancer cells promote evolvability, generating lethal cancer

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor—natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly‐aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure—without the eradication of the resilient PACCs, cancer will recur in treated patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156440/2/eva12929_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156440/1/eva12929.pd

Predicting Responses of Geo-ecological Carbonate Reef Systems to Climate Change: A Conceptual Model and Review

[Chapter Abstract] 230Coral reefs provide critical ecological and geomorphic (e.g. sediment production for reef-fronted shoreline maintenance) services, which interact in complex and dynamic ways. These services are under threat from climate change, requiring dynamic modelling approaches that predict how reef systems will respond to different future climate scenarios. Carbonate budgets, which estimate net reef calcium carbonate production, provide a comprehensive ‘snap-shot’ assessment of reef accretionary potential and reef stability. These budgets, however, were not intended to account for the full suite of processes that maintain coral reef services or to provide predictive capacity on longer timescales (decadal to centennial). To respond to the dual challenges of enhancing carbonate budget assessments and advancing their predictive capacity, we applied a novel model elicitation and review method to create a qualitative geo-ecological carbonate reef system model that links geomorphic, ecological and physical processes. Our approach conceptualizes relationships between net carbonate production, sediment transport and landform stability, and rates knowledge confidence to reveal major knowledge gaps and critical future research pathways. The model provides a blueprint for future coral reef research that aims to quantify net carbonate production and sediment dynamics, improving our capacity to predict responses of reefs and reef-fronted shorelines to future climate change.https://nsuworks.nova.edu/occ_facbooks/1116/thumbnail.jp

Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation

Chapter 4 PREDICTING RESPONSES OF GEO-ECOLOGICAL CARBONATE REEF SYSTEMS TO CLIMATE CHANGE: A CONCEPTUAL MODEL AND REVIEW

oceanography, climate change, reefs, marine science, marine conservation, marine researc

Primer sequences for the amplification of RT-PCR products from canine cell lines.

<p>Primer sequences for the amplification of RT-PCR products from canine cell lines.</p

Cancer stem cells are resistant to the cytotoxic effects of doxorubicin.

<p>Spheres were isolated from the canine osteosarcoma cell lines; KTOSA5 (A) and CSKOS (B), and the human osteosarcoma cell lines U2OS (C) and SAOS2 (D). Spheres and adherent cells were treated with the indicated doses of doxorubicin and cell viability was assayed 48 hr after treatment (* <i>p</i><0.005).</p

Spheres are resistant to replicative cell death after doxorubicin treatment.

<p>Colony forming ability after doxorubicin treatment was determined in KTOSA5 cells (* <i>p</i> = 0.008; ** <i>p</i><0.001) (A) and U2OS cells (♮ <i>p</i> = 0.008; ♮♮ <i>p</i><0.001) (B).</p

Gene expression analysis of canine osteosarcoma stem cells.

<p>A three-dimensional representation of a principle component analysis of expression microarray data derived from KTOSA5 adherent cells, spheres and mesenchymal stem cells (MSC) (A). Heirarchial clustering analysis of the expression data (cut off p-value of 0.005). Expression values are represented by colours: blue squares represent low-expressed genes, red squares represent high-expressed genes (B). Biological process analysis of differentially expressed genes in KTOSA5 spheres compared to adherent cells (FDR = 0.005) (C).</p

Top biological functions of differentially expressed genes in KTOSA5 spheres compared to adherent cells (FDR = 0.005).

<p>Top biological functions of differentially expressed genes in KTOSA5 spheres compared to adherent cells (FDR = 0.005).</p

COX-2 inhibition suppresses sphere forming ability.

<p>KTOSA cells were pre-treated for 24 hr with the indicated doses of meloxicam prior to assaying for sphere forming ability (* <i>p</i><0.001) (A). KTOSA5 (B), CSKOS (C), U2OS (D) and SAOS2 (E) cells were pre-treated for 24 hr with the long-acting COX-2 inhibitor mavacoxib prior to assaying for sphere forming ability (* <i>p</i><0.001).</p