Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

Abstract

Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting. Paschos KA, Majeed AW, Bird NC. Natural history of hepatic metastases from colorectal cancer -pathobiological pathways with clinical significance.

Comparative analysis of CD4 and CD8 lymphocytes — evidences for different distribution in primary and secondary liver tumors

“…It was noted that TAMs play important role in tumor development and progression in liver [47]. TAMs are lured and activated by cancer cells, which secrete either M-CSF (macrophage colony stimulating factor) [47] or/and CEA (carcinoembryonic antigen) [52]. Our previous report showed that number of TAMs in LM was associated with overall survival (OS) [53].…”

Macrophage profile in primary versus secondary liver tumors

“…Recent data presented the modulatory role of hepatic microenvironment both in initiation and progression of the primary carcinogenic process as well as in establishment of optimal conditions for metastatic colonization and development [5,12,21,26]. A necessary condition for HCC initiation and development seems to be the presence of activated inflammatory cells in the liver, through their action on signaling pathways, which results in enhanced cellular turnover and acquisition of critical modifications for the malignant transformation [27,28].…”

“…It was reported in HM that highly aggressive Dukes C and D malignant cells of CRC-origin can trigger apoptotic death of TAMs and monocytes by the secretion of high mobility group box 1 (HMGB1) protein [38]. On the other hand, malignant cells can attract TAMs by secretion of carcinoembryonic antigen (CEA) followed by the release of growth factors by enticed macrophages [21].…”

“…On the other hand, TAMs association to an improved postoperative survival and their role as positive prognostic factor in HCC were supported by other research groups [15,16]. In the studies of TAMs involvement in the development of hepatic metastases (HM), the most numerous were related to the colorectal cancer (CRC)-associated metastases [17][18][19][20][21]. Similarly to HCC, macrophages in HM can act against metastatic cells in a direct cytotoxic way or by secretion of TNF and proteases [22], however, TAMs can also support survival and differentiation of malignant cells via secretion of growth factors [23] or metalloproteinases [24].…”

Premetastatic niche formation in the liver: emerging mechanisms and mouse models

“…For one, the liver is connected via the blood circulation to those sites where many malignant tumours arise [18]. In addition, the healthy liver actually displays intrinsic architectural and functional features, whose balance can easily be tipped towards favouring metastasis to this organ [9,19,20], even without priming by factors secreted by the original tumour site, as it would be the case in classic premetastatic niche formation. They comprise the following: (1) the liver-specific microcirculation with its unique sinusoidal cell population, (2) the perivascular mesenchymal cells including hepatic stellate cells (HSCs), (3) the morphologically and metabolically heterogeneous parenchymal cell compartment, and (4) the hepatic regional immunity (Fig.…”