Chemoreceptors as a key to understanding carcinogenesis process

Journal Pre-proof Chemoreceptors as a key to understanding carcinogenesis process Leszek Satora, Jennifer Mytych, Anna Bilska-Kos, Katarzyna Kozioł

PII:

S1044-579X(19)30230-5

DOI:

https://doi.org/10.1016/j.semcancer.2019.10.003

Reference:

YSCBI 1691

To appear in:

Seminars in Cancer Biology

Received Date:

3 July 2019

Revised Date:

4 October 2019

Accepted Date:

4 October 2019

Please cite this article as: Satora L, Mytych J, Bilska-Kos A, Kozioł K, Chemoreceptors as a key to understanding carcinogenesis process, Seminars in Cancer Biology (2019), doi: https://doi.org/10.1016/j.semcancer.2019.10.003

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Chemoreceptors as a key to understanding carcinogenesis process *

Leszek Satoraa, Jennifer Mytychb, Anna Bilska-Kosc and Katarzyna Koziołb

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Pomeranian Center of Clinical Toxicology Kartuska 4/6, 80-104 Gdansk, Poland.

Department of Animal Physiology and Reproduction, University of Rzeszow, Werynia 502,

36-100 Kolbuszowa, Poland. Department of Plant Biochemistry and Physiology, Plant Breeding and Acclimatization

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Institute - National Research Institute, Radzików, 05-870 Błonie, Poland

*

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Corresponding author

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Dr Leszek Satora

Tel: +48 682 19 39

Abstract:

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E-mail address: [email protected]

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Pomeranian Center of Clinical Toxicology Kartuska 4/6, 80-104 Gdansk, Poland.

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The tissue organization field theory (TOFT) presented completely new, different from the previous one, perspective of research on neoplasm processes. It implicates that secretory neuroepithelial-like cells (NECs), putative chemoreceptors, are probably responsible for the control of squamous epithelial cells proliferation in digestive tract during hypoxia in gut breathing fish (GBF). On the other hand, chemoreceptors dysfunction can lead to uncontrolled proliferation and risk of cancer development in mammals including humans. The studies on

NECs like cells (signal capturing and transduction) may be crucial for understanding the processes of controlling the proliferation of squamous epithelial cells in the digestive tract of GBF fish during hypoxia states. This knowledge can contribute to the explanation of cancer processes.

Keywords: chemoreceptors: carcinogenesis; gut breathing fish; squamous cells proliferation;

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TOFT theory

Introduction

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Otto Warburg was the first to show, that neoplasm has a higher rate of glucose

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metabolism than other tissues. He described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions (Warburg effect). Recent studies arguing that

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cancer cells benefit from this phenomenon and the discussion on its role in the carcinogenesis

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Background

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processes have been lately resumed (Koppenol et al., 2011).

Sonneschein and Soto (2016) proposed a new theory, the tissue organization field

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theory (TOFT), for explanation of carcinogenesis, according which cancer is a problem of tissue organization similar to histogenesis and organogenesis. The authors suggest that proliferation with variation and motility is the default state of all cells. Release of the constraints created by cell interactions and the physical forces generated by cellular agents stimulate cells within a tissue to regain their default state. Therefore, not only molecules but also biophysical forces generated by the cells and the tissues are important in both

morphogenesis and carcinogenesis. According to this theory, the search for factors responsible for maintaining the equilibrium within the cells of organism is crucial for understanding the carcinogenesis process. Warming and the extremely high biological demand for O2 imposed by the crowding and decomposition of the organic material can lead to hypoxia in the habitats of the late Silurian, which probably led to the development of air breathing among ‘early’fish, as well as the emergence of tetrapods in Devonian period (Graham, 1997). On the other hand, the effect of water hypoxia is the strongest impulse for

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Cell proliferation in gut breathing fish during hypoxia period

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breathing air among contemporary fish (Graham, 1997).

There are extremely interesting species among the air-breathing fish (ABF) – gut

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breathing fish (GBF) adapting their digestive tract to the function of an additional respiratory organ in waters with low oxygen concentration (Graham, 1997, Nelson, 2014). It has been

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suggested that during hypoxia in GBF fish there is the phenomenon of 'epithelial remodelling' consisting in the multiplication of squamous cells and thereby the creation of sites in the

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gastrointestinal tract allowing diffusion of gases (Satora et al., 2019). In this process, hypoxia inducible factor 1α (HIF-1α) and epidermal growth factor receptor (EGFR) are involved. Our

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previous studies have shown the presence of HIF-1α and EGFR in the respiratory part of

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intestine in Corydoras aeneus (Satora et al., 2017; Mytych et al., 2018; Satora et al., 2018). The suggested process of proliferation of squamous cells could contribute to the formation of lung terrestrial vertebrates, and it was consolidated. In ‘epithelial remodelling’ in GBF fish the both processes may be involved: Epithelial-mesenchymal transition (EMT) and Mesenchymal-epithelial transition (MET). During EMT, epithelial cells lose their differentiated phenotypes and become mesenchymal-like cells, which have greater ability to migrate and proliferate (Kalluri and Weinberg, 2009). HIFs are stabilized under hypoxic

conditions (Veith et al., 2016) and can promote the activation ligand-independent EGFR signalling (Wang et al., 2012), what induces EMT (Misra et al., 2012). Whereas, EMT alters the proliferative potential of cells by modulating ERBB3 expression - a member of the EGFR family. The downregulation of ERBB3 after EMT affects phosphoinositide 3-kinase (PI3K)dependent proliferation. Changes in EMT status can rewire signalling upstream of cell proliferation (Salt et al., 2014). Furthermore, the mesenchymal cells may differentiate into various epithelial cell types during MET process (Pei et al., 2019). However, a detailed

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examination of the mechanisms of dependence of metabolic profiles and cellular phenotypes as well as the regulation of the fate of the cells in the proliferation are necessary to explain the

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epithelial remodelling process.

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Polymodal chemoreceptors

Vertebrate have evolved mechanisms to detect changes of oxygen level during periods

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of hypoxia which play a key role in adjusting oxygen delivery to the metabolic needs of the cells and tissues (Jonz et al., 2016). A polymodal chemoreceptors in vertebrates are

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specialized structures capable of detecting several sensory modalities including: O2, CO2 and/or H+, ammonia, hypoglycemia and numerous other (Milsom, 2002; Zaccone et al., 2006;

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Zaccone et al., 2011; Jonz, 2018). Chemoreceptive cells mediating responses to hypoxia have

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been identified in mammalian and aquatic vertebrates (water- and air-breathing fish). Secretory neuroepithelial cells (NECs) of the gill filaments are involved in sensing and transforming the chemical signal about hypoxia in fish. The carotid body type I cells in mammals are a paired structure located within the neck. Also, in lungs of this group of vertebrates a clusters of cells called neuroepithelial bodies (NEBs) are embedded within the airway epithelium (Zaccone et al., 2011; Jonz, 2018). Both of them (NEBs and carotid body cells) are sensitive to low P O2 and undergo K+ channel inhibition under these conditions

(Jonz, 2018). NEBs are also sensitive to CO2, H+ and hypercapnia (Lauweryns et al., 1977). NEB cells, presumed polymodal airway sensors, produce a variety of peptides and bioactive amines, that have local or distant effects, but the precise function of these cells is currently unknown (Jonz, 2018). It is suggested that NEBs are important in the fetal and neonatal lungs as regulators of airways development. Moreover, there is a connection between specific types of lung cancer and NEBs (Van Lommel, 2001). Secretory NECs having similar biochemistry and morphology to carotid body type I cells and pulmonary NEBs, have been identified in the

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fish gill, therefore homologues between them have been proposed (Dunel-Erb et al., 1982). Probably the NECs chemoreceptors are responsible for triggering the proliferation/apoptosis of the interlamellar cell mass during the remodelling of the gill present in some fish species

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(Nilsson, 2007; Tzaneva et al., 2011). It has been also assumed that oxygen chemoreceptors played an important role in stimulating the development of organs for air-breathing in the

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early terrestrial vertebrates (Smatresk, 1990; Jonz 2018). A similarity between the cell

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hyperplasia (cellular proliferation) observed in carcinogenesis (recognized as a major factor in human liver cancer) and proliferation of a single type of cell in fish processes has also been

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described (Iwanowicz, 2011).

Numerous studies have confirmed that in O2 sensitive neurosecretory cells (carotid

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body type I cells, cells in the neuroepithelial bodies of the lung) acute responses to hypoxia are mediated by ion channels. In these cells, a well-studied effect of hypoxia is the inhibition

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of oxygen‐sensitive potassium channels causing membrane depolarization, activation of voltage gated Ca2+ channels followed by influx of Ca2+ , what activates and/or inhibits different intra- and/or extra-cellular signalling pathways (Lopez-Barneo et al., 2004; 2001). The deregulation of K+ signalling is associated with a variety of diseases, including cancer. High expression of potassium channel family, which are involved in the cell proliferation, survival, angiogenesis, migration, and invasion, has been shown in many types of cancer. In

addition, K+ channels have been proposed to interfere with hypoxia homeostasis by increasing basal HIF-1α activity and lowering the threshold of HIF-1α activation by hypoxia (Felipe et al., 2006; Pardo and Stühmer 2014; Ouadid-Ahidouch et al., 2016). In the sensing of hypoxic stimuli in pulmonary neuroendocrine cells/neuroepithelial bodies (PNECs-NEBs) in mammals, including humans, a key role plays TASK-1 (TWIK-related acid-sensitive potassium channel 1) (Olschewski et al., 2017). TASK-1 comprises the acid- and oxygensensitive two-pore domain channels and regulates the resting membrane potential, as well as

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the signal in smooth muscle cells of the pulmonary arteries, intestine, and bladder (Patel and Honoré, 2001; Olschewski 2010). TASK-1 is expressed not only in the normal lung tissue,

but also in non-small cell lung cancer (NSCLC) and small cell lung carcinoma (SCLC) cell

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line H-146. In a highly TASK-1-expressing lung cancer cell lines, it promotes cellular

proliferation and inhibits apoptosis (Cutz et al., 2013; Leithner et al., 2016). Interestingly,

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TASK-1 induces EGFR tyrosine kinase inhibitors (TKIs) resistance by promoting cancer cell

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formation and epithelial‑ mesenchymal transition in lung cancer, what favours lung cancer

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cell invasion and metastasis (Rho et al., 2009; Li et al., 2016; Wang et al., 2018).

Putative chemoreceptors – new hope

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Cells described as NECs having morphological features resembling those of

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chemoreceptors of the gills, in the respiratory epithelium of the air-breathing structure of the lungfishes, bichirs, bowfins of some catfish species have been described (Zaccone et al., 2006; Zaccone et al., 2011, Zaccone et al., 2018). Also, the simultaneous occurrence of NECs and NEBs in the respiratory gas bladder of a Lepisosteus has been found (Zaccone et al., 2011). The secretory activity of this structures was verified by the cytosolic labelling with specific antibodies against 5-HT (Zaccone, et al., 2011). It has been demonstrated that, in

most air-breathing fish, O2 chemoreceptors of the gills control the net level of ventilation of the gills and ABOs (Smatresk, 1990; Burggren and Pan, 2009). However, there is evidence for internal O2 receptors in some species (McKenzie et al., 1991; Hedrick and Jones, 1999). The studies on GBF fish using a transmission electron microscope (TEM) showed the presence of NEC cells like chemoreceptors in Ancistrus multispinnis, Plecostomus hypostomus and Corydoras aeneus (Satora and Winnicki, 2000; Podkowa and Witalińska, 2002; Podkowa and Witalińska, 2003). It is assumed, that in addition to their digestive role,

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they may play a role in the control of the breathing process. However, the studies on the

whole spectrum of chemicals stimuli to which membrane receptors respond tuned to the

necessary (Zaccone et al., 2018; Jonz, 2018).

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different neurotransmitters types, and on the physiological role of these responses are

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The currently somatic mutation theory of carcinogenesis and metastases (SMT) sets the direction for experimental research on cancer (Sonneschein and Soto, 2011). In contrast,

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TOFT theory suggests a completely different design of experimental research. According to this, the molecular mechanisms of oxygen chemoreception (under normal and hypoxic

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conditions) in airways chemoreceptors in lung carcinoma seem to be very interesting. Also, the experimental scheme allowing inhibition and/or stimulation of the proliferation markers

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and the signal emitted by neuroepithelial like cells seems to be an important next stage of

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research on gut breathing fish.

In conclusion, the epithelial remodelling and squamous cell formation in GBF fish

appear to be initiated by chemo-sensitive cells with specific ion channels. Under hypoxia, these cells receive and transmit a signal initiating the proliferation of squamous cells. In mammals, including humans, dysregulation and/or chemoresistance of chemoreceptors may lead to uncontrolled proliferation and risk of cancer development. Hence, GBF fish may be a

new natural model for the study of O2-sensitive cells which also characterizes lung cancer

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cells in vivo.

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