Gastrin-releasing peptide links stressor to cancer progression

Abstract

Introduction: Gastrin-releasing peptide (GRP) plays an important role in cancer growth and metastasis; however, the mechanisms of how GRP affects cancer progression are not well understood. Recent studies revealed that chronic stress is a major risk factor for cancer progression, and this effect may be mediated by GRP. In this review, we will discuss the mechanisms and implications of GRP linking stressor to cancer progression.

Materials and methods: We retrieved the studies of the relationship between GRP, stress and cancers through PubMed using systematic methods to search, select, and evaluate the findings.

Results: The results suggested that GRP can mediate the effects of stress on cancers at systemic, tissue and cellular levels: Stress elicits the secretion of GRP in the brain and GRP in turn activates the stress response pathways resulting in an elevation of stress hormones and GRP in the plasma and tissues. GRP in synergy with stress hormones stimulates the growth and invasion of cancer cells by suppressing the anti-tumor immune function and directly activating the pro-proliferative and pro-migratory signaling pathways in cancer cells.

Conclusion: GRP is a multi-functional peptide, which acts as a stress mediator as well as a growth factor linking stressor to cancer progression. GRP and its high-affinity receptor are useful targets for the diagnosis and treatment of cancers.

Fig. 1

Systemic mechanisms of GRP linking stressor to cancer progression: Upon stressor exposure, GRP is released from the hypothalamus and adrenal medulla, subsequently activates CRH and AVP neurons, and therefore activates the PHA axis and ANS. Chronic stressor exposure results in chronic elevated stress hormones and GCs in plasma, and decouples the peripheral circadian rhythms from the control of central circadian clock, settles a neuroendocrine manner of cancer growth. In addition, GRP secreted from neighboring neuroendocrine cells and tumor cells targets the GRPR on tumor cells to stimulate growth and metastasis in paracrine and autocrine manners

Fig. 2

Intracellular signals of GRPR stimulation in cancer cells: The intracellular signals of GRPR stimulation are not well understood so far. Recent proposed mechanisms involve: GRPR couples either to Gq or Gα12/Gα13 protein, or through transactivation of RTKs via a MMPs-dependent cleavage of heparin-binding epidermal growth factor, resulting in activation of multiple signaling pathways in cancer cells (Marinissen and Gutkind 2001)