PAK in Pancreatic Cancer-Associated Vasculature: Implications for Therapeutic Response

Abstract

Angiogenesis has been associated with numbers of solid tumours. Anti-angiogenesis drugs starve tumours of nutrients and oxygen but also make it difficult for a chemo reagent to distribute into a tumour, leading to aggressive tumour growth. Anti-angiogenesis drugs do not appear to improve the overall survival rate of pancreatic cancer. Vessel normalisation is merging as one of the new approaches for halting tumour progression by facilitating the tumour infiltration of immune cells and the delivery of chemo reagents. Targeting p21-activated kinases (PAKs) in cancer has been shown to inhibit cancer cell growth and improve the efficacy of chemotherapy. Inhibition of PAK enhances anti-tumour immunity and stimulates the efficacy of immune checkpoint blockades. Inhibition of PAK also improves Car-T immunotherapy by reprogramming the vascular microenvironment. This review summarizes current research on PAK's role in tumour vasculature and therapeutical response, with a focus on pancreatic cancer.

Keywords: angiogenesis; chemotherapy; immunotherapy; p21-activated kinases (PAKs); pancreatic cancer; vessel normalisation.

Figure 1

Factors contributing to abnormal tumour vasculature. One of the essential components within the tumour microenvironment (TME) is the existence of abnormal vascular structures. Abnormal blood vessel growth, leaky vessel, loss of pericyte support, and low levels of oxygen are primary characteristics of these blood vessels. These features are interconnected and can mutually enhance the abnormalisation of blood vessels. For instance, a hypoxic microenvironment triggers the production of VEGF, which in turn reinforces the growth of abnormal blood vessels [27].

Figure 2

Anti-angiogenesis vs. vascular normalisation. The conventional treatment of cancer with anti-angiogenesis drugs is associated with negative outcomes. Despite limiting the amount of nutrition delivered to cancer cells, it can also increase hypoxia, resulting in increased metastasis. Drug delivery to the tumour site can also be restricted by anti-angiogenesis. Alternatively, vascular normalisation can reduce levels of hypoxia and enhance the tumour infiltration of immune cells and drug delivery to the tumour site. To normalise tumour vasculature and limit tumour growth, restoring pericyte support is essential. It has been demonstrated in PDA models that increasing pericyte coverage can reduce hypoxia and increase drug delivery [38].

Figure 3

Activation and functions of PAKs in pancreatic cancer. PAK1 and PAK4 act downstream of KRas, stimulate cell proliferation, epithelial–mesenchyme transition (EMT), and migration/invasion, and contribute to abnormal vasculature and immune suppression.

Figure 4

Significance of the effects of PAKs on tumour vasculature in cancer treatment.