<300 μm; undetectable
0.3–0.5 mm; a few are detectable
>5 mm; detectable
Produce certain effects on focal liver
Produce systemic effects and may give rise to extrahepatic spread
Location and status
Confined within the hepatic lobule, free of angiogenesis, or only small amount of microvessel formations
It occupies the whole hepatic lobule and grows outward, with obvious angiogenesis
Clinically visible metastasis has been formed
Relation with liver cellsa
Have not recruited vascular and interstitial components
Recruited liver cells and formed the mesenchyme and blood vessels of metastatic tumor
Affected by two aspects, the liver cells of normal liver beside the cancer and the liver cells infiltrated in the cancer
Effects on the liver
Only affect the liver cells in the colonized location
Jointly developing with the liver cells recruited into the cancerous focus
Affect normal hepatic tissue and structure, blood supply, and parenchymal molecular metabolism
Proinflammatory cytokines, immunosuppressive factor, stimulating factors of fibroblasts, oxidative stress-induced factors
Angiogenic factors, myelomonaytic growth factor (CMGF)
Tumor growth promotion factors, immunosuppressive factors
The contrasts between the surrounding liver tissue of metastasis and the normal liver distant from the metastasis have revealed that such genetic expressions as “extracellular matrix”, “intercellular communication”, “activation of astrocytes”, and “cell growth” of paracarcinoma liver tissue are markedly upregulated, thus indicating the cancer-causing function of paracarcinoma hepatic microenvironment . The spectrum of specific gene expression originated from paracarcinoma hepatic tissue or the interstitial cells in the metastasis can predict metastasis recurrence and patients’ survivals after metastasis resection.
4.3 Problems and Outlook
4.3.1 The Value of Microenvironment in Tumor Prevention and Cure
Tumor microenvironment plays an important role in tumor progression, tumor interstitium as antitumor target has obvious advantages, and if the interstitial cells are non-transformation cells, compared with tumor cells, their genome is relatively stable and they have a small chance of antigen loss and therapeutic tolerance; interstitial cells have little differences on different tumors, and therapy targeting at tumor interstitium can be used on various kinds of solid tumors on a wide spectrum.
The value of prevention is far greater than that of therapy. Various kinds of cells (macrophages, endothelial cells, fibroblasts, etc.) in the tumor microenvironment are all effective targets that can be prevented. First, the impacts on various kinds of anti-inflammatory treatments on TAM and TAN are quite obvious, for they are the main source of inflammatory mediators. Secondly, for the T lymphocytes of microenvironment, the mouse model has proven that the key molecules SMAD that selectively knock the TGF-β signaling pathways in T lymphocytes can lead to the defuse malignancy of the whole digestive tract; however, the mere selective knockout of the SMAD in the epithelial cells has no such effect ; at the early stage of the occurrence of human digestive tract tumor, it is also possible to detect the loss of TGF-β signaling pathways; drugs that can restore or strengthen the TGF-β signaling pathways mediated by SMAD can enhance the expression of downstream products (such as plasminogen activator inhibitor-1, TGFβR2) and inhibit the malignant transformation of canceration, indicating the prevention application value of the T lymphocytes of microenvironment . In addition, various kinds of small molecule substances in the microenvironment, corresponding signaling pathway genes, and the formation of tumor vessels can all be taken as targets of prevention. Among them, the representative ones include the drugs that reconstruct the immune microenvironment with the relevant factors of antagonistic immune tolerance, such as small molecule substances of the major molecular mechanisms tolerant to microenvironment indoleamine 2, 3-dioxygenase (IDO), Arg, arginase I, inducible nitric oxide synthase (iNOS), and JAK-STAT signaling pathways. These drugs can activate the DC in patients, myeloid-derived suppressor cells (MDSCs), and CTL, recruit them in large amounts to the local microenvironment, and simultaneously block the cell-regulating functions of TAM and TAN .
The spontaneous treatment of microenvironment during the treatment of cancerous cells has become two undividable aspects of microenvironment treatment. After the plantation of cancerous cells with high invasion and metastasis potentials into the embryonic microenvironment, not only the cancerous cells manifest relatively better differentiation characteristics, even similar to the corresponding cells derived from normal sources, but also the capacity of nodule formation and invasion and metastasis is substantially reduced, indicating the shaping role of normal embryonic microenvironment on cancerous cells and its potential application value . The balance between promoting and anti-angiogenic factors in the microenvironment makes the angiogenesis abnormal, and vessel structures tend to become normalized, thus correcting the abnormal metabolic state of microenvironment (pH values, gap pressure, and hypoxia) and restoring the sensitivity to chemoradiotherapy, etc. Research has indicated there exists an instantaneous “normalization window” in the angiogenesis therapy based on VEGFR2 antibodies, and the curative effects of combination therapies during this window are far greater than those of combination therapies of non-window period, indicating the importance of prolonging the vascular “normalization window” period and time selection in combination therapies . The hindrance of tumor interstitium is considered as one of the reasons for the poor curative effects of antitumor immunity. Promoting the release of stromal antigens using such means as chemoradiotherapy, thus inducing the CTL reactions regarding the stromal antigen, or killing the interstitial cells with cross-presentation of tumor antigens, or stimulating the double immune responses from both antitumor and interstitial resistant cells, will be more conducive to the elimination of tumors and prevention of tumor recurrence .
4.3.2 Several Notable Aspects
Although tumor microenvironment is conducive to tumor progression, there still exists a certain balance relationship between the tumor suppressor factors and promoting factors in the microenvironment. Matrix degradation enzymes play an active role in the process of the formation and invasion and metastasis of blood vessels, but the endostatin, angiostatin, and tumstatin as the degradation products of MMPs are the main endogenous vascular resultants; therefore the experimental and clinical wide-spectrum MMPs have limited curative effects. Therefore, the development of specific inhibitors and the selections of specific patients and appropriate therapeutic targets (whether inhibiting the cellular functions or killing the cells) must be considered regarding the treatment of tumor microenvironment.
Selecting appropriate therapeutic targets and promoting the normalization of the abnormal tumor microenvironment are usually more effective. Excessive formation of tumor-inhibiting vessels can not only correct the abnormal angiogenesis but can also induce the tumors’ resistance to angiogenesis and worsen the abnormalities of local vascular structure, thus worsening such metabolic disturbances as hypoxic microenvironment and uneven distribution of nutrients and the increase of the tumor cells’ tolerance to chemoradiotherapy and capacity of invasion and metastasis. If it is dedicated to restoring the vascular structure of the tumor microenvironment and thus bringing about sufficient and evenly distributed oxygen and nutrient supply, it will not only give growing advantages to tumor cells with weaker tolerance to such adverse conditions as hypoxia and lower malignant biological characteristics, thus competitively inhibiting cancerous cells with relatively higher malignancies, but also is more beneficial for follow-up or simultaneous therapy focused on the tumor’s invasion and metastasis, which is successively or simultaneously conducted, to play its role .
Although combination therapy is superior to monotherapy, if the design of combined application is inappropriate, on the contrary it will have exactly opposite effects. The dedication to immunologic tolerance of antagonistic microenvironment and reconstruction of the regulatory means conducive to antitumor immunity microenvironment, if rationally combining such traditional antitumor therapies as chemoradiotherapy, can play the synergistic and additive effects. Regarding radiotherapy, radiotherapy can promote the microenvironment’s function of antigen-presenting cells and induce the T-cell infiltration, yet at present, for such reasons as the reduction of toxicity, clinically fractionated radiotherapies are more commonly adopted, so what kind of effects this will bring on the immune response induced by the first local irradiation and whether the radiotherapy interval or one-time large-intensity local irradiation must be considered in the combined reconstruction of local immune microenvironment.
In addition, the study of tumor microenvironment must have good models. In the embryonic microenvironment models utilizing zebrafish embryos and chicken embryos, it is found that normal embryonic microenvironment has reversal effect on the malignant characteristics of cancerous cells, the total control mechanism of embryonic stem cells, and highly malignant tumor cells and their potential application values. The development of the economical and efficient models applicable to different research objectives and maximally simulating the in vivo microenvironment will greatly enhance the development of tumor microenvironment study.
4.3.3 Hepatic Microenvironment and the Prevention of Liver Metastasis of Intestinal Cancer
Hepatic microenvironment plays an important role in the hepatic directional metastasis of intestinal cancer; the normal anatomical characteristic wherein blood flows into the liver from the intestines via the portal vein is unchangeable, and the spontaneously discovered intestinal cancer and liver metastasis are also irreversible. However, for those who are not subject to liver metastasis, we can alter the hepatic microenvironment so as to prevent the occurrence of liver metastasis of intestinal cancer, or halt the reactivation of the intestinal cancerous cells that have been colonized and in dormant state, or prevent the post-metastasectomy relapse. The sinusoidal endothelial cells of hepatic microenvironment, astrocytes, immune and inflammatory cells, and hepatic parenchymal cells are all targets that can be tried. Specific chemokines and their receptors, such as CCR6 and CCL20 axis, as well as the newly discovered CCL2 , are also very good targets.
Currently, a new hypothesis, “pre-metastatic niche,” holds that before the tumor cells arrive at the target organs, they will release several factors to activate hematopoietic progenitor cells (HPCs), and these cells will reach the target organs before the tumor cells, creating a microenvironment there that is suitable for the survival and proliferation of metastatic tumor cells so as to receive the arrival of tumor cells. The significance of this hypothesis for the liver metastasis of intestinal cancer may lie in the fact that the synergy of HPC and hepatic microenvironment promotes the occurrence of liver metastasis, and it also provides new challenges and opportunities to therapies targeting at hepatic microenvironment.
Bross IDJ, Blumenson LE. Metastatic sites that produce generalized cancer: identification and kinetics of generalizing sites. In: Fundamental aspects of metastasis. 1976. p. 359–75.
Sugarbaker EV. Patterns of metastasis in human malignancies. Cancer Biol Rev. 1981;2:235–78.