Cancer as a Disease of Homeostasis: An Angiogenesis Perspective

Kareva, Irina

doi:10.1016/b978-0-12-804310-3.00019-3

Cited by 4 publications

(7 citation statements)

References 47 publications

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“…Most if not all adaptations that are observed in cancer progression have normal equivalents, which are either engaged by cancer in the wrong context (i.e., cell migration), or start normally but become pathological (i.e., wound healing becoming angiogenesis [ 19 , 20 , 21 ], or transient immune suppression during wound healing or pregnancy [ 22 , 23 ]). While starvation is a natural suspect for such an equivalent to cachexia, the metabolic alterations occurring in starvation are qualitatively different [ 17 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology

Kareva

2022

Cells

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Cancer cachexia is one of the leading causes of mortality for late-stage cancer patients. One of its key characteristics is abnormal metabolism and loss of metabolic flexibility, i.e., loss of ability to switch between use of fats and carbohydrates as needed. Here, it is hypothesized that late-stage systemic cancer creates a chronic resource drain on the body that may result in the same metabolic adaptations that occur during intense endurance exercise, activating some of the same mechanisms of nutrient consumption that are supposed to be transient during strenuous physical activity. This hypothesis is evaluated by creating a mathematical model that characterizes the relationships between increased exercise intensity and carbohydrate and fat oxidation. The model is parametrized using published data on these characteristics for a group of professional athletes, moderately active individuals, and individuals with metabolic syndrome. Transitions between different zones of relative nutrient consumption as a function of increased effort are captured through explicitly modeling ventilatory thresholds, particularly VT1 and VT2, where fat is primarily used below VT1, both carbohydrates and fats are used between VT1 and VT2, and where carbohydrates become the primary source of fuel above VT2. A simulation is conducted of projected patterns of nutrient consumption when simulated “effort” remains between VT1 and VT2, or above VT2, and it is proposed that it is the scenario when the simulated effort is maintained primarily above VT2 that most closely resembles metabolic patterns characteristic of cachexia. A discussion of a broader framework for understanding cachectic metabolism using insights from exercise physiology, including potential intervention strategies, concludes this paper.

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Section: Discussionmentioning

confidence: 99%

Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology

Kareva

2022

Cells

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“…Figure 5 The proportion of simulated patients that achieve tumor elimination (ranging from 0% eliminated in blue to 100% eliminated in yellow) across a simulated population. This population has F_2, the in ammatory threshold of transition between reversible to terminal exhaustion, uniformly distributed between [15,35].…”

Section: Declarations Con Icts Of Interestmentioning

confidence: 99%

Mitigating non-genetic resistance to checkpoint inhibition based on multiple states of immune exhaustion

Kareva,

Gevertz

2023

Preprint

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Despite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance, remain significant challenges. Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. The emerging understanding is that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that it is inflammation induced by drug activity that triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together, is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.

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“…Following the emergence of premalignant lesions, the survival of cancer clusters relies on increased production of angiogenesis stimulators, such as vascular endothelial growth factor (VEGF), that attract nutrient and oxygen providing blood vessels to the growing tumors (Bremnes, Camps, & Sirera, ; Carmeliet, ; Peterson et al, ). If two tumors induce production of angiogenesis stimulators, it is likely that eventually a threshold will be reached, such that the host would respond with increased production of angiogenesis inhibitors (e.g., platelet factor 4 [PF‐4], thrombospondin‐1 [TSP1], and endostatin), to counteract systemic increase in angiogenesis stimulators, which may be sufficient to restrict the growth of the smaller secondary tumors (Kareva, ). Interestingly, TSP1 is over‐expressed in obese patients (Varma et al, ), and this phenomenon may contribute to the obesity paradox.…”

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confidence: 99%

“…[TSP1], and endostatin), to counteract systemic increase in angiogenesis stimulators, which may be sufficient to restrict the growth of the smaller secondary tumors (Kareva, 2017). Interestingly, TSP1 is over-expressed in obese patients (Varma et al, 2008), and this phenomenon may contribute to the obesity paradox.…”

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Obesity paradox in cancer: Is bigger really better?

Újvári

Jacqueline

Missé

et al. 2019

Evolutionary Applications

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While obesity is widely recognized as a risk factor for cancer, survival among patients with cancer is often higher for obese than for lean individuals. Several hypotheses have been proposed to explain this “obesity paradox,” but no consensus has yet emerged. Here, we propose a novel hypothesis to add to this emerging debate which suggests that lean healthy persons present conditions unfavorable to malignant transformation, due to powerful natural defenses, whereby only rare but aggressive neoplasms can emerge and develop. In contrast, obese persons present more favorable conditions for malignant transformation, because of several weight‐associated factors and less efficient natural defenses, leading to a larger quantity of neoplasms comprising both nonaggressive and aggressive ones to regularly emerge and progress. If our hypothesis is correct, testing would require the consideration of the raw quantity, not the relative frequency, of aggressive cancers in obese patients compared with lean ones. We also discuss the possibility that in obese persons, nonaggressive malignancies may prevent the subsequent progression of aggressive cancers through negative competitive interactions between tumors.

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Cancer as a Disease of Homeostasis: An Angiogenesis Perspective

Cited by 4 publications

References 47 publications

Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology

Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology

Mitigating non-genetic resistance to checkpoint inhibition based on multiple states of immune exhaustion

Obesity paradox in cancer: Is bigger really better?

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