Cancer Letters

Cancer Letters

Volume 296, Issue 2, 28 October 2010, Pages 144-149
Cancer Letters

Mini-review
Prokineticins in angiogenesis and cancer

https://doi.org/10.1016/j.canlet.2010.06.011Get rights and content

Abstract

This review will examine the roles of prokineticins in the different neoplasms that have been investigated and will discuss how and why the prokineticin family presents such interesting prospects in the research against cancer. Prokineticins belong to a family of highly conserved small peptides (8 kDa) discovered a decade ago in frog skin secretions and snake venom. The mammalian orthologs consist of two prokineticin peptides, prokineticin 1 (PROK1) and prokineticin 2 (PROK2) that signal through two G-protein coupled receptors: prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Over the last decade of research, the PROK/PROKR system has been associated with a considerable number of physiological and pathological functions. Due to this wide spectrum of functions, notably potent angiogenic and immunoregulatory activities, numerous investigators have researched the PROK/PROKR system’s role in cancer development in a variety of tissues.

Introduction

Prokineticins belong to a family of multifunctional chemokine-like peptides [1] that were discovered a decade ago in the cutaneous secretions of the yellow-bellied toad (Bombina variegata), and in the venom of the Black Mamba (Dendroaspis polylepis) [2], [3]. Pharmacological characterization of the amphibian peptide B. variegata 8 (Bv8) and its reptilian ortholog Mamba Intestina Toxin-1 (MIT-1) demonstrated similar intestinal contractile activity on rodents. Subsequently, identification and characterization of the human orthologs for MIT-1 and Bv8 showed a similar capacity to induce gastrointestinal motility. Thus, based on this common function present across species, this new family of proteins was baptized prokineticins (peptides that cause movement of the intestines) and accordingly MIT-1 was renamed prokineticin 1 (PROK1) and Bv8 renamed prokineticin 2 (PROK2) [4].

The following decade of research on this family of peptides revealed a complex system consisting of two ligands (PROK1 and PROK2) that bind with similar range of affinity to two cognate 7-transmembrane G-protein-coupled receptors (PROKR1 and PROKR2) [5]. The prokineticins are highly conserved among species, and are characterized by an N-terminal AVIT consensus sequence as well as 5-disulfide bonds – present in all members of this family. Prokineticins weigh approximately 8 kDa, are highly basic peptides and can sequester in the extracellular matrix. Prokineticins and their receptors are distributed in a variety of human tissues (ovary, testis, adrenal gland, placenta, uterus, brain, intestinal tract, heart, bone marrow and peripheral blood) [6]. Their regulation and cellular distribution vary greatly from tissue to tissue and display a wide range of tissue-specific biological activities. They are able to coordinate complex behaviors such as feeding, drinking, circadian rhythm, and hyperalgesia, but are also involved in neuron migration and survival, angiogenesis, haematopoiesis and inflammation.

Even though the mammalian prokineticin ligand/receptor system includes only two ligands and two receptors, it demonstrates a great diversity of biological functions. This diversity stems from the fact that prokineticins seem to have distinct regulation, are distributed differentially in tissues, and that ligands have a non-specific affinity for their receptors and can activate multiple signaling events. In the context of their role in neoplasm pathophysiology, which is the main focus of this review, they have elicited great interest among cancer investigators because of their role as survival factors for certain tissue-specific cells, and for their ability to induce angiogenesis and coordinate a pro-inflammatory immune response (see Fig. 1).

Section snippets

Angiogenic properties of the prokineticins in physiology and pathophysiology

Prokineticins participate actively in physiological angiogenesis in numerous tissues of the body, and in some cases participate in neoplastic angiogenesis. They are known to influence normal angiogenesis in the adrenal gland, pancreas, ovary, testis, endometrium, placenta, and heart. The first angiogenic properties of prokineticins were observed ex vivo and in small animal models. Delivery of prokineticins into ovary, testis or retina of rodents resulted in a strong angiogenic response as

Colorectal cancer

The potential implication of prokineticins was investigated in colorectal cancer. In a panel of 113 resected colorectal cancers, PROK1 transcripts were detected in only 31 cases. However, positive expression of PROK1 was more often associated with a lower survival rate and metastasis [21]. In a complementary study, colorectal cancer cell lines expressed PROK1 significantly, whereas in human normal mucosae PROK1 was undetected. Implantation in mice of a colorectal cancer cell line (SW620)

Conclusion

Prokineticins can participate actively in the tumorigenesis process (prostate, testicles, neuroblastoma, colon, and pancreas) where they participate as a growth factor for cancer cells, an angiogenic and a chemotactic factor for pro-inflammatory neutrophils. Prokineticins could be implicated in other cancers not yet investigated, such as brain cancer, where they serve as very important growth factors for nerve cells of the olfactory bulb [5], or potentially in leukemias since they are expressed

Conflicts of interest

None declared.

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