Macro- and Micro-environmental Factors in Clinical Hepatocellular Cancer

Abstract

We previously developed a network phenotyping strategy (NPS), a graph theory-based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm×n (S) and 22 cm×n (L), p<10−14. The means of survival distribution (not available previously) for this new cohort were also significantly different (S was 12 months, L was 7 months, p<10−5). We characterized nine unique reference patterns of interactions between tumor and clinical environment factors, identifying four subtypes for S- and five subtypes for L-phenotypes, respectively. In L phenotype, all reference patterns were PVT (portal vein thrombosis) positive, all platelet/AFP levels were high, and all were chronic alcohol consumers. L had phenotype landmarks with worst survival. S phenotype interaction patterns were PVT negative, with low platelet/AFP levels. We demonstrated that tumor-clinical environment interaction patterns explained how a given parameter level can have a different significance within a different overall context. Thus, baseline bilirubin is low in S1 and S4, but high in S2 and S3, yet all are S subtype patterns, with better prognosis than in L. Gender and age, representing macro-environmental factors, and bilirubin, INR and AST levels representing micro-environmental factors, had a major impact on subtype characterization. Clinically important HCC phenotypes are therefore represented by complete parameter relationship patterns and cannot be replaced by individual parameter levels.

An HCC Aggressiveness Index and Blood GTP, Bilirubin and Platelet Levels

“…It has long been accepted that growing HCC tumor masses can destroy or replay liver parenchyma and thus enhance liver damage. There is now evidence that the converse is also likely true and that liver micro environmental factors may influence HCC growth and invasion [12][13][14][15][16][17][18][19]. Molecular signatures of the underlying liver in HCC patients provide support for this idea [25][26][27], as well as recently reported clinical associations of changes in liver function with HCC biology [3].…”

“…As a result, elements of both sets of factors are included in most HCC classification and prognostication systems [10] with increasing refinements [11]. The underlying liver has been increasingly understood as a complex dynamic of cells, tissues, inflammatory cytokines and growth factors [12][13][14][15][16][17][18]. This has been most extensively studied with respect to the neo vascular endothelial cells that form the blood vessels that are needed to support the growing tumor mass, and are an important target for various multikinase inhibitors, which are used in cancer therapy.…”

“…Two general categories of inflammation can be discerned in cancer in general, including HCC. They are: (a), local, micro environmental inflammation [17,18], such as that associated with chronic hepatitis [19]; and (b), systemic inflammation, as measured by blood C-reactive protein and albumin levels in the Glasgow and similar inflammation-based prognostic scoring systems [4][5][6]20]. Some micro environmental cell types have multiple functions, such as platelets, which are involved in blood coagulation, metastasis [21], and hepatitis B immune modulation [22], HCC cell growth and migration [23] and the production of HCC growth stimulants [24].…”

Inflammatory Mechanisms of HCC Development

“…Our recent results supported a primary role of EGF and IGF-I in interfering with the inhibitory action of Sorafenib and Regorafenib in HCC cell lines [48][49][50] (Figure 2). Moreover, growing data show that the modulatory actions of platelet factors such as EGF (epidermal growth factor), IGF-I (insulin-growth factor-I), TGF-β (transforming growth factor beta), PDGF and VEGF (vascular endothelial growth factor) alter the cancer chemotherapy sensitivity or resistance [47]. Our recent results supported a primary role of EGF and IGF-I in interfering with the inhibitory action of Sorafenib and Regorafenib in HCC cell lines [48][49][50] (Figure 2).…”

CD40 in coronary artery disease: a matter of macrophages?

“…Environmental differences like these are important in tumor progression [ 111 , 113 ], but there is also indirect evidence that these environmental differences play a role in other diseases. For example, the lack of apoptosis of macrophages inside the atheromatous plaque is thought to aggravate atherosclerosis [ 88 , 146 ].…”