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Biomedical subjects

R A Gatenby

Publications and source records attributed to R A Gatenby.

At least 19 recordsLinked to original sources
PubMed2003

Microenvironmental and cellular consequences of altered blood flow in tumours.

Tumour angiogenesis is triggered by various signals characteristic of the tumour microenvironment, including low oxygen tension, low extracellular pH and low glucose concentration. Tumour microvasculature is chaotic, producing perfusion heterogeneities which can be visualized by MRI and other modalities. Inefficient perfusion in tumours produces regions of transient and chronic hypoxia. Tumour hypoxia is associated with adverse clinical outcomes and reduced patient survival. Hypoxia may be a factor in activation of extracellular matrix-degrading proteases, and some studies have correlated primary tumour hypoxia with likelihood of tumour cell dissemination. Exposure to hypoxia either induces or selects for cells that are hyperglycolytic, and this in turn produces local acidosis which is also a common feature of solid tumours. Increased glucose uptake in hyperglycolyzing tumour cells is the basis of lesion-visualization in positron emission tomography using 18F-fluorodeoxyglucose. Tumour acidity can reduce the effectiveness of weak-base drugs, but can be exploited to increase the anti-tumour activity of weak-acid chemotherapeutics. Evidence linking tumour acidity with increased activity of several extracellular matrix-degrading enzyme systems is examined. High levels of lactate, another end-product of glycolysis, in primary lesions have been correlated with increased likelihood of metastasis. In the numerous studies correlating hypoxia, acidity and lactate with metastasis, the direction of the causality has not been adequately established. We hypothesize that adoption of a hyperglycolytic phenotype is a necessary feature of carcinogenesis itself, and confers a survival and proliferative advantage to tumour cells over surrounding normal cells. Empirical evidence supporting this "acid-mediated tumour invasion" model is discussed.

Cell Hypoxia↗
PubMed2001

A cellular automaton model of early tumor growth and invasion.

A hybrid cellular automaton model is described and used to simulate early tumor growth and examine the roles of host tissue vascular density and tumor metabolism in the ability of a small number of monoclonal transformed cells to develop into an invasive tumor. The model incorporates normal cells, tumor cells, necrotic or empty space, and a random network of native microvessels as components of a cellular automaton state vector. Diffusion of glucose and H(+)ions (the latter largely resulting from the tumor's excessive reliance on anaerobic metabolism) to and from the microvessels, and their utilization or production by cells, is modeled through the solution of differential equations. In this way, the cells and microvessels affect the extracellular concentrations of glucose and H(+)which, in turn, affect the evolution of the automaton. Simulations of the model demonstrate that: (i) high tumor H(+)ion production is favorable for tumor growth and invasion; however for every H(+)ion production rate, there exists a range of optimal microvessel densities (leading to a local pH favorable to tumor but not to normal cells) for which growth and invasion is most effective, (ii) at vascular densities below this range, both tumor and normal cells die due to excessively low pH, (iii) for vascular densities above the optimal range the microvessel network is highly efficient at removing acid and therefore the tumor cells lose their advantage over normal cells gained by high local H(+)concentration. While significant spatial gradients of glucose formed, no regions of detrimentally poor glucose perfusion (for either cell type) were observed, regardless of microvessel density. Depending on metabolic phenotype, a variety of tumor morphologies similar to those clinically observed were realized in the simulations. Lastly, a sharp transition (analogous to that of the adenoma-carcinoma sequence) between states of initial tumor confinement and efficient invasiveness was observed when H(+)production reached a critical value.

Biological Transport↗
PubMed2001

Mathematical models of tumour invasion mediated by transformation-induced alteration of microenvironmental pH.

The invasive phenotype, characteristic of malignancy, is found in multiple transformed populations with widely varying genotypes. The authors hypothesize that this genetic heterogeneity and instability precludes mechanisms of tumour invasion requiring consistent, coordinated production of one or more proteins or other macromolecules. Instead, this model assumes that the genetically disordered, unstable populations found in tumours must employ a simple mechanism of invasion that arises from one common trait of all transformed cells--reversion to a phenotype more primitive (less differentiated) than the tissue of origin. Specifically, this approach focuses on primitive metabolic pathways with preferential use of glycolysis for energy production. Mathematical models of invasive cancer based on tumour-induced acidification of the microenvironment are presented. Using population ecology and diffusion-reaction models, it is shown that normal tissue adjacent to the tumour edge is subjected to an extracellular pH that is significantly lower than normal. This leads to degradation of the interstitial matrix, loss of intercellular gap junctions and cell necrosis. Tumour cells have an optimal extracellular pH less than that of normal cells and are thus able to thrive in the acidic microenvironment expanding into the space of the dying normal tissue. The model is consistent with extant data on the tumour microenvironment as well as clinical data relating increasing tumour invasiveness with elevated glucose utilization and lactate content. It predicts well-established phenomena in tumorigenesis such as the adenoma-carcinoma sequence and the critical role of angiogenesis in the invasive phenotype. An acellular gap at the tumour host interface is also predicted and can be demonstrated in pathologic specimens. Novel treatment approaches based on this model are discussed.

Extracellular Space↗
PubMed1999

Carcinogenesis and the plasma membrane.

Presented is a two-stage hypothesis of carcinogenesis based on: (1) plasma membrane defects that produce abnormal electron and proton efflux; and (2) electrical uncoupling of cells through loss of intercellular communication. These changes can be induced by a wide variety of stimuli including chemical carcinogens, oncoviruses, inherited and/or acquired genetic defects, and epigenetic abnormalities. The resulting loss of electron/proton homeostasis leads to decreased transmembrane potential, electrical microenvironment alterations, decreased extracellular pH, and increased intracellular pH. This produces a positive feedback loop to enhance and sustain the proton/electron efflux and loss of intercellular communication. Low transmembrane potential is functionally related to rapid cell cycling, changes in membrane structure, and malignancy. Intracellular alkalinization affects a variety of pH-sensitive systems including glycolysis, DNA synthesis, DNA transcription and DNA repair, and promotes genetic instability, accounting for the accumulation of genetic defects seen in malignancy. The abnormal microenvironment results in the selective survival and proliferation of malignant cells at the expense of contiguous normal cell populations.

Animals↗
PubMed1999

Brachytherapy in early prostate cancer--early experience.

Use of brachytherapy with radioactive seeds in the management of early prostate cancer is commonly used in the United States. The early experience has been reported from the prostate treatment centers in Seattle for the last 10 years. In this manuscript we are reporting our early experience of 150 radioactive seed implantations in early stage prostate cancer using either Iodine 125 or Palladium 103 seeds. The average age of the patient is 66 years and the median Gleason score is 5.4 with a median PSA of 6. A brief description of the evolution of the treatment of prostate cancer as well as the preparation for the seed implantation using the volume study with ultrasound of the prostate, pubic arch study using CT scan of the pelvis and the complete planning using the treatment planning computers are discussed. We also have described the current technique which is used in our experience based on the Seattle guidelines. We plan a follow-up report with the results of the studies with longer follow-up.

Aged↗
PubMed1998

Imaging advances in the diagnosis of endocrine neoplasia.

Endocrine neoplasms are rare tumors that have traditionally been imaged with ultrasound, CT, magnetic resonance imaging, and angiography. Additional imaging modalities are now available. Endoscopic ultrasound is a new imaging approach to islet cell tumors of the pancreas, in which they typically appear round, homogeneous, and slightly hypoechoic compared with the pancreatic parenchyma. Carcinoid tumors can now be localized with 111In octreotide scintigraphy, which binds to the somatostatin receptors in the tumor. Pheochromocytomas have a distinctive appearance on magnetic resonance imaging, but important advances have occurred using 131I metaiodobenzylguanidine (MIBG). 131I MIBG scanning has a high diagnostic accuracy in detecting pheochromocytoma, with sensitivity greater than 90%. The various tumors and recent advances in their imaging are discussed.

Carcinoid Tumor↗
PubMed1996

A reaction-diffusion model of cancer invasion.

We present mathematical analyses, experimental data, and clinical observations which support our novel hypothesis that tumor-induced alteration of microenvironmental pH may provide a simple but complete mechanism for cancer invasion. A reaction-diffusion model describing the spatial distribution and temporal development of tumor tissue, normal tissue, and excess H+ ion concentration is presented. The model predicts a pH gradient extending from the tumor-host interface, which is confirmed by reanalysis of existing experimental data. Investigation of the structure and dynamics of the tumor-host interaction within the context of the model demonstrates a transition from benign to malignant growth analogous to the adenoma-carcinoma sequence. The effect of biological parameters critical to controlling this transition are supported by experimental and clinical observations. Tumor wave front velocities determined via a marginal stability analysis of the model equations are consistent with in vivo tumor growth rates. The model predicts a previously unrecognized hypocellular interstitial gap at the tumor-host interface which we demonstrate both in vivo and in vitro. A direct correlation between the interfacial morphology and tumor wave front velocity provides an explicit, testable, clinically important prediction.

Carcinoma, Squamous Cell↗
PubMed1996

Application of competition theory to tumour growth: implications for tumour biology and treatment.

To assess critical parameters controlling tumour growth and response to therapy, competition theory models the tumour-host interface as a network of interacting normal and malignant cell populations using coupled, non-linear differential equations. When the equations are analysed under conditions which simulate tumour development, three phases of tumour growth, each with different critical parameters, can be predicted. Transitions between these phases correspond to the initiation, promotion and invasion stages demonstrated in experimental models of carcinogenesis. Critical cellular properties for each transition are predicted including phenomena already demonstrated experimentally such as the linkage of invasive tumour growth with acquisition of angiogenesis. The model also predicts the previously unknown phenomenon of "functional equivalence" in which disparate tumour traits can play identical roles in tumour growth and invasion. This approach allows the diverse but inconsistent properties of transformed cells to be understood according to their specific contribution to tumorigenesis. The models have significant implications for treatment strategies.

Cell Division↗
PubMed1996

Malignant plasmacytoma appearing as invasive paranasal sinus disease after cardiac transplantation.

Invasive plasmacytoma appearing as a mass in the paranasal sinuses developed in two patients after cardiac transplantation. Radiographic findings included a sinus mass with bony invasion and expansion. The findings were radiographically indistinguishable from common malignant neoplasms and aggressive infectious processes. Malignant plasmacytoma should be considered in the differential diagnosis of invasive paranasal sinus masses in chronically immunosuppressed patients.

Aged↗
PubMed1995

Models of tumor-host interaction as competing populations: implications for tumor biology and treatment.

Population ecology mathematical models examine tumors not as an isolated collection of transformed individuals but as part of a dynamic society of interacting malignant and normal cells. This approach investigates the mechanisms by which a small clone of neoplastic cells is able to replace the much larger and previously stable population of normal cells, despite the numerical advantage of the latter and the inhibitory effects of the host response. The models define a sequence of different stable equilibria with critical mathematical parameters which control the outcome of different stages of the neoplasm-host competition--parameters which can be correlated with cellular physiologic properties. When neoplasm is viewed as a network of interacting tumor and normal populations, a unifying hypothesis can be developed that allows the diverse but inconsistent properties of transformed cells to be understood according to their specific contributions to tumorigenesis within this network. It predicts general sequences of genetic changes necessary for tumor survival and invasion and demonstrates that apparently disparate properties found in different tumor models can be functionally equivalent. The paper proposes novel modes of therapy requiring classification and treatment of tumors according to the strategies they employ, rather than the traditional criteria of cell type and organ of origin.

Cell Survival↗
PubMed1995

The potential role of transformation-induced metabolic changes in tumor-host interaction.

Increased glycolysis in transformed cell coupled with increased membrane Na+/H+ exchange produces significant environmental fluctuations in and around tumors, including enhanced local glucose consumption and based competition model that examines the effects of these environmental changes on tumor-host interaction. By generating a critical parameter (J) for each population at the tumor-host interface, the interactive dynamics can be predicted. Although necessarily limited by simplifying assumptions, the model demonstrates that the metabolic changes of transformation and their environmental consequences could confer significant advantages on tumor populations by decreasing their J value and, through the generation of glucose and pH gradients, increasing the J value of adjacent normal cells. Thus, the well-documented metabolic changes associated with transformation, including increased glycolysis, glucose utilization, and lactic acid production with reversal of the normal intracellular-extracellular pH gradient, phenomena now consistently demonstrated in human tumors in situ, provide a potential mechanism of tumor invasion that is simple, complete, and sufficiently general to apply to many classes of tumors. The model explicitly predicts that in situ measurement of tumor glucose utilization and H+ production will determine prognosis. Furthermore, it predicts therapies that chronically reduce tumor glucose utilization and/or H+ production or increase the buffering capacity in normal tissue will be effective in tumor prevention and tumor treatment.

Animals↗
PubMed1995

Potential role of FDG-PET imaging in understanding tumor-host interaction.

UNLABELLED: Population ecology mathematical models of tumorigenesis have been developed to define the cellular characteristics which allow a transformed population to begin as a single individual but end with complete destruction of the host. To invade and expand, a tumor population must compete successfully with normal cells for space and critical, shared substrate such as glucose. This study uses population ecology models to examine the potential role of competition for glucose in tumor biology and its implications for FDG-PET imaging. METHODS: Chemostat population ecology mathematical models of the tumor-host interface are developed resulting in coupled, nonlinear differential equations which link population growth to acquisition and utilization of glucose. RESULTS: The models demonstrate that increased FDG uptake in tumors observed on PET imaging is the result of increased consumption necessary to provide surplus energy for reproduction when inefficient glycolytic pathways are used for glucose metabolism. Specific parameters of the glucose consumption curves are predicted to be markedly different in normal and neoplastic tissues and critical to the tumor-host interaction. Tumor invasability and patient prognosis can be linked to these parameters. CONCLUSION: The mathematical models link FDG-PET imaging with processes fundamental to the outcome of the tumor host interaction. The value of FDG-PET can be expanded by quantitation of glucose uptake parameters which will be highly specific in tumor detection and strong indicators of tumor aggressiveness. Therapeutic modalities designed to decrease tumor glucose uptake or increase glucose uptake in normal tissue could be directed and monitored by FDG-PET.

Deoxyglucose↗
PubMed1994

Monitoring substrate uptake and distribution by tumors using percutaneous catheters and solid nuclear track detectors.

RATIONALE AND OBJECTIVES: This study was designed to test a new technique for measuring intratumoral drug and substrate concentrations using a modified percutaneous catheter and solid nuclear track detectors. MATERIAL AND METHODS: A nephrostomy catheter was modified to allow exposure of the lumen of the catheter to adjacent tissue and placed percutaneously in a 4047 colon cancer growing in the flank of a Fischer 344 rat. Measurement of metabolite distribution was obtained using carbon-14-labeled deoxy-d-glucose and multiple strips of CR-39 (a solid nuclear track detector) placed sequentially in the catheter to measure the low energy beta emissions from the carbon-14. RESULTS: The administered deoxy-d-glucose initially distributed to the vascularized rim of the tumor, but rapidly defused down concentration gradients into the necrotic core. CONCLUSION: The preliminary data suggest that this technique is feasible. Further validation studies may show that this technique may allow for monitoring of temporal and spatial variations in the distribution of drugs and metabolites within tumors.

Animals↗
PubMed1992

Identification of a novel cell population in nonhealing wounds in tumors.

We have explored wound healing in tumors as a possible model for tumor-host interaction. This work demonstrated tumor wound healing failure to be the result of intense inhibition of fibroblasts although the tumor cells did not appear to be the direct source of the inhibitors. The inflammatory infiltrate found in tumor wounds was then examined for possible sources of the observed fibroblast suppression. Although the tumor wound infiltrate contains cell populations similar to a normal wound infiltrate, it also contains a large, vacuolated, nonadherent, phagocytic mononuclear cell which has morphologic and cytochemical characteristics of a lipid-laden macrophage. However, the cell also proliferates under normal culture conditions and has an immunophenotype more characteristic of lymphocytes than those of macrophages with striking expression of the CD8 surface antigen. Conditioned media from this cell population markedly inhibit fibroblast proliferation suggesting it is the source of fibroblast inhibitors within the tumor wound. Mechanical dissociation of non-wounded tumors yielded evidence that the tumor wound cell is normally present in small numbers within the tumor.

Animals↗
PubMed1991

Population ecology issues in tumor growth.

Mathematical models developed from population ecology are applied to tumor-host interactions and demonstrate the importance of increased efficiency in substrate absorption as a mechanism enabling tumor cells to (a) proliferate despite inefficient energy production and (b) compete successfully for resources with the numerically superior host cells. As with many biological invasions observed in nature, success of the invaders can be enhanced by disruption of the local ecology if the disruption results in decreased viability of the native populations reducing their ability to inhibit tumor cell growth either directly through an immunological response or indirectly by competition with the tumor cells for available resources. Following successful invasion and displacement of normal cells from a volume of tissue, tumor cells achieve new equilibrium states with the environment based on their efficiency of consumption and the vascularity of the tissue. Tumor therapy may be enhanced by reducing available resources below a level which will support growth of the tumor cells or above a threshold which will allow repopulation by normal cells.

Animals↗
PubMed1991

Percutaneous catheter drainage for malignant pericardial effusion.

Ultrasound (US)-guided and fluoroscopically guided pericardial catheter placement was performed in 12 patients with known underlying malignancy who had clinical and radiographic evidence of a significant pericardial effusion. US guidance facilitated placement of a 22-gauge needle by means of a subxyphoid or transthoracic approach. The tract was subsequently dilated over a wire under fluoroscopic guidance with placement of either an 8.5- or 10-F catheter. This technique successfully established pericardial drainage in all patients with excellent symptomatic relief. Cytologic findings were positive for malignancy in 10 of the 12 patients. Radiologically guided pericardiocentesis allowed safe, rapid stabilization of the condition of patients with symptoms from pericardial effusion. This resulted in excellent palliation in patients with terminal disease and improvement in the clinical status of other patients so that additional therapies, such as sclerosis with tetracycline or surgical placement of a pericardial window, could be performed on an elective basis.

Adult↗
PubMed1991

Corporate-sponsored breast cancer screening at the work site: results of a statewide program.

Mobile screening mammography was offered to 3,627 employees of a large corporation in Pennsylvania and Delaware. The examination was available to women employees or employee spouses aged 35 years and older. Women were charged $30 for a standard two-view examination. They also received health education materials on mammography and breast self-examination. The remaining costs of the program were underwritten by the corporation. During this program, 3,627 mammographic studies were performed; 63 biopsies were recommended. Fifty-seven biopsies were performed, and nine cancers were diagnosed. Costs of this program are presented in detail. The authors conclude that mobile screening programs at the work site provide an inexpensive, convenient alternative to more traditional screening programs. The inherent advantages of this program are the low cost, the relative ease with which the examination can be performed, and the positive role that corporate medical personnel assume in encouraging individual and group participation.

Adult↗