Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Abstract

Malignant melanoma cells are incredibly hardy, stemming from their intrinsic defensive nature. These cells inherit unique characteristics, which allowed their non-malignant predecessors, melanocytes, to survive solar ultraviolet radiation and simultaneously provide protection to neighboring cells. Most other cell types would die after such harsh exposure. Unsurprisingly, melanoma cells, which survive ultraviolet radiation, are intrinsically resistant to most chemotherapy. Although there are numerous molecular reasons for this reality, herein we focus on the causal role of autotaxin (ATX) in melanoma. ATX is a 125 kDa glycoprotein enzyme that was initially discovered in the serum-free medium of A2058 human melanoma cells by Stracke et al. in 1992 [1] (Figure 1). Today, we know much more about this glycoprotein enzyme and how it affects melanoma. Indeed, ATX is highly overexpressed among primary melanomas and metastatic melanomas, in comparison to melanoma in situ and in normal skin [2]. In fact, "autotaxin" derived its name based on its initial property as an "autocrine motility factor". The rationale is that A2058 melanoma cells secrete ATX into culture medium and then respond to it with self-stimulated random and directed motility. Even though the amount of ATX in conditioned medium is less than 0.005% of total protein, only miniscule amounts, detected in picomolar and nanomolar concentrations, are needed to promote motility. [1] This suggests a large role for a low-abundant secreted enzyme. There are five alternatively-spliced isoforms of ATX that are catalytically active [3,4]. The original ATX protein described in 1992 is termed ATXα, whereas the most abundant isoform is ATXβ and is the same isoform responsible for plasma lysoPLD activity [5]. Full length ATX

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…In some cancers, such as melanoma, glioblastoma, and thyroid, ATX is secreted directly by the cancer cells [65,66]. This increased ATX activity is hijacked in cancers (wounds that do not heal) to promote a chronic inflammatory state leading to the secretion of a milieu of pro-growth and survival inflammatory mediators [21,67,68].…”

“…Breast cancer cells, however, produce little ATX [66,[78][79][80] as do kidney, stomach, lung, ovarian, colorectal, and pancreatic cancer cells ( Figure 2). In these cancers, the tumor microenvironment is instead the primary source of ATX.…”

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

“…We have further demonstrated a key role for the breast adipose tissue in these events. Notably, breast cancer cells produce very little ATX [27][28][29]. Instead, ATX is secreted by breast adipocytes and this activity increases in response to inflammation caused by cytokines produced by an adjacent breast tumor [30][31][32][33].…”

Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

“…Our group developed a new paradigm for understanding breast tumor progression and treatment. Breast cancer cells produce insignificant quantities of ATX, which, instead, is produced by tumor‐associated stroma and adjacent breast adipose tissue (26, 27). Inflammatory cytokines from breast tumors facilitate high expression of ATX and LPA during chronic inflammation as they override the feedback inhibition of ATX synthesis by LPA (17, 28).…”