Arrowhead Parmaceuticals, Madison, WI 53719, USA; University of Wisconsin, Madison, WI 53705, USA; University of Pittsburgh, Pittsburgh, PA 15260, USA.
Med Hypotheses. 2019 May;126:109-128. doi: 10.1016/j.mehy.2019.03.019. Epub 2019 Mar 25.
Unlike other carcinomas, hepatocellular carcinoma (HCC) metastasizes to distant organs relatively rarely. In contrast, it routinely metastasizes to liver vasculature/liver, affecting portal veins 3-10 times more often than hepatic veins. This portal metastatic predominance is traditionally rationalized within the model of a reverse portal flow, due to accompanying liver cirrhosis. However, this intuitive model is not coherent with facts: 1) reverse portal flow occurs in fewer than 10% of cirrhotic patients, while portal metastasis occurs in 30-100% of HCC cases, and 2) portal vein prevalence of HCC metastasis is also characteristic of HCC in non-cirrhotic livers. Therefore, we must assume that the route for HCC metastatic dissemination is the same as for other carcinomas: systemic dissemination via the draining vessel, i.e., via the hepatic vein. In this light, portal prevalence versus hepatic vein of HCC metastasis appears as a puzzling pattern, particularly in cases when portal HCC metastases have appeared as the sole manifestation of HCC. Considering that other GI carcinomas (colorectal, pancreatic, gastric and small bowel) invariably disseminate via portal vein, but very rarely form portal metastasis, portal prevalence of HCC metastasis appears as a paradox. However, nature does not contradict itself; it is rather our wrong assumptions that create paradoxes. The 'portal paradox' becomes a logical event within the hypothesis that the formation of the unique portal venous system preceded the appearance of liver in evolution of chordates. The analysis suggests that the appearance of the portal venous system, supplying hormones and growth factors of pancreatic family, which includes insulin, glucagon, somatostatin, and pancreatic polypeptide (HGFPF) to midgut diverticulum in the early evolution of chordates (in an Amphioxus-like ancestral animal), promoted differentiation of enterocytes into hepatocytes and their further evolution to the liver of vertebrates. These promotional-dependent interactions are conserved in the vertebrate lineage. I hypothesize that selective homing and proliferation of malignant hepatocytes (i.e., HCC cells) in the portal vein environment are due to a uniquely high concentration of HGFPF in portal blood. HGFPF are also necessary for liver function and renewal and are significantly extracted by hepatocytes from passing blood, creating a concentration gradient of HGFPF between the portal blood and hepatic vein outflow, making post-liver vasculature and remote organs less favorable spaces for HCC growth. It also suggested that the portal vein environment (i.e., HGFPF) promotes the differentiation of more aggressive HCC clones from already-seeded portal metastases, explaining the worse outcome of HCC with the portal metastatic pattern. The analysis also offers new hypothesis on the phylogenetic origin of the hepatic diverticulum of cephalochordates, with certain implications for the modeling of the chordate phylogeny.
不同于其他癌种，肝细胞癌（HCC）向远处器官转移相对较少。相比之下，它通常向肝血管/肝脏转移，门静脉转移的发生率比肝静脉转移高 3-10 倍。这种门静脉转移的优势传统上可以用逆门静脉血流模型来解释，这是由于伴随的肝硬化所致。然而，这种直观的模型与事实并不一致：1）逆门静脉血流在不到 10%的肝硬化患者中发生，而 HCC 转移在 30-100%的 HCC 病例中发生；2）非肝硬化肝脏中的 HCC 转移也以门静脉转移为主。因此，我们必须假设 HCC 转移扩散的途径与其他癌种相同：通过引流血管（即肝静脉）进行全身扩散。从这个角度来看，HCC 转移的门静脉优势与肝静脉优势的比例似乎令人费解，特别是在门静脉 HCC 转移仅作为 HCC 唯一表现的情况下。考虑到其他 GI 癌种（结直肠癌、胰腺癌、胃癌和小肠癌）无一例外地通过门静脉转移，但很少形成门静脉转移，HCC 转移的门静脉优势似乎是一个悖论。然而，大自然不会自相矛盾；是我们错误的假设造成了悖论。在假设中，独特的门静脉系统的形成先于脊索动物肝脏的出现，“门静脉悖论”成为一个合乎逻辑的事件。分析表明，在脊索动物早期进化中（在类似文昌鱼的祖先进化动物中），供应胰腺家族激素和生长因子（包括胰岛素、胰高血糖素、生长抑素和胰多肽（HGFPF））的门静脉系统的出现，促进了中肠憩室的肠上皮细胞分化为肝细胞，并进一步演化为脊椎动物的肝脏。这些与促进相关的相互作用在脊椎动物谱系中是保守的。我假设，恶性肝细胞（即 HCC 细胞）在门静脉环境中的选择性归巢和增殖是由于门静脉血液中 HGFPF 的浓度特别高。HGFPF 对于肝功能和更新也是必需的，并且会从通过的血液中被肝细胞大量提取，从而在门静脉血液和肝静脉流出之间形成 HGFPF 的浓度梯度，使肝后血管和远处器官成为 HCC 生长不太有利的空间。这也表明门静脉环境（即 HGFPF）促进了已播散的门静脉转移中更具侵袭性的 HCC 克隆的分化，这解释了具有门静脉转移模式的 HCC 预后更差的原因。该分析还为头索动物的肝憩室的系统发生起源提供了新的假设，对脊索动物系统发生的建模具有一定的启示意义。
