Xiong-Zhi WuTianjin Medical University Cancer Institute and Hospital, Tianjin 300070, China.

Abstract The proceeding of cancer development seems to be driven by the complex interaction among cells, stroma and adjacent tissue. Here we advocate a new conception, cancer field, to describe the development of cancer, a complex adaptive system. Cancer field may be divided into center of tumor, periphery of tumor and adjacent tissue. The balance of inhibitors and inducers, including the interaction among cancer cells, niche and adjacent tissue, governs the switch of development of cancer field, which mimic embryonic development, a dynamic process of self-organization. The radial component of intra-tumor heterogeneity raises the field change effects in cancer field. Research strategy may be changed from single cancer cell to cancer field, from malignant transform to cancer development biology.

Keywords: Cancer field, Self-organization, Carcinogenesis, Heterogeneity, Niche

Background

After the recent past century, researches have generated a complex scientific literature about carcinogenesis. In 2000, Hanahan and Weinberg listed "hallmarks" of cancer that must be considered in order to understand the underlying determinants of carcinogenesis: (a)self-sufficiency in growth signals; (b) insensitivity to growth-inhibitory signals; (c) evasion of programmed cell death; (d) limitedless replicative potential; (e) sustained angiogenesis; and (f) tissue invasion and metastasis [1].In addition, aggressive tumor cells are phenotypically plastic and sharing many properties with embryonic cells[2-4].Moreover, the proceeding of forming neoplam seems to be driven by the complex interaction among cancer cells, stroma and adjacent tissue. To portray the central biological reality of tumor formation, conceptual change is need to understand the complexities of the disease, which governs the transformation of normal cells into malignant tissues. Here we advocate a new conception, cancer field, to describe the complex adaptive system. Cancer field may be divided into center of tumor,periphery of tumor and adjacent tissue. The balance of inhibitors and inducers, including the interaction among cancer cell, niche and adjacent tissue, governs the switch of development of cancer field, which mimic embryonic development, a dynamic process of self-organization. The radial component of intratumor heterogeneity raise the field change effects in cancer field.

Search strategy and selection criteria

We tried to identify all relevant studies irrespective of language. We searched PubMed, Medline, and Current Contents with a combination of the following terms:“self-organization”, “carcinogenesis”, “heterogeneity”,“stroma”, “host”, “niche”, “extracellular matrix”,“microenvironment”, “embryonic”, “development” and“adjacent tissue”. Studies were selected on the basis of recent contributions to the understanding of the cellular and molecular basis of carcinogenesis. Most searches covered 2000-07, but earlier papers were also included.

Self-organization and cancer development

The primary principles of carcinogenesis may be self-organization. Self-organization is a process where the organization of a system spontaneously increases without being guided or managed by otherwise external system.Cancer tissue is made up by many types of cells (such as cancer cells, stromal fibroblasts, immune cells and bone marrow stem cells), tissues (such as blood vessel, nerve and lymphatic vessel) and extracellular matrix. The transformed cell has the property of attracting many types of cells to form cancer field. Tumor is typical composed by cancer cells with a wide variety phenotype whereas the interstitial cells have a defined phenotype. The proceeding of forming cancer field, a complex adaptive system, seems to be driven by self-organization [5-8].

By controlling the interaction between cells and their embedding matrices, embryonic development is the result of a dynamic process of self-organization [9-12].Aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells, such as undifferentiated nature, ability for proliferation, resistance to apoptosis, angiogenesis, propensity for invasion and metastasis, expression of embryonic antigen [2, 13-14].Recent advances in the understanding of the role of Wnt pathway, Hedgehog, Notch, PAR and Bone morphogenetic peptide/TGF beta signaling pathways in the embryonic development have shed new light on carcinogenesis [3, 4, 15-21]. Thus cancer may arise because the developmental programs that create the dramatic alterations in form and structure in embryonic development are potentially corrupted [21]. Owing to the similarities between embryonic and cancerous development, carcinogenesis proceeds may misappropriate homeostatic mechanisms that many oncogenes play an important role of embryonic development. Many features of cancer become much clearer when viewed within the context of our model: the proceeding of forming cancer field - namely, cancer development - mimic embryonic development, a dynamic process of self-organization, which governs the a single cell into tissues. To portray the central biological reality of tumor formation, research strategy may be changed from malignant transform to cancer development biology.

Figure 1 The balance of inhibitors and inducers for cancer field

Cancer development may be regulated both by inducers and inhibitors. The balance of inhibitors and inducers governs the switch of cancer development. In some cases, the activation of cancer field inducers may keep the switch on, while in others the cancer field inducers are present but held in check by higher levels of cancer field inhibitors. Thus, either reducing the inhibitor concentration or increasing the activator levels can each change the balance and activate the switch, leading to forming cancer field.

Cancer development can be regulated both by inducers and inhibitors. The balance of inhibitors and inducers governs the switch of formation of cancer field (Figure 1).Inhibitors and inducers may be divided into intracellular factors, such as oncogenes and tumor suppressor genes,and extracellular factors, the interaction among cancer cells, niche and adjacent tissue. For instance, the appearance of genetic instability of oncogenes and tumor suppressor genes are critical for carcinogenesis.According to the genetic model of tumorigenesis, gene mutation and epigenetic events are the cause of cancer.Tumor progression is driven by a sequence of mutations in a limited number of genes (causality). Gene mutations,which are ordered in time, are related to the emerging phenotypic traits of malignant cells (determinism) [6, 22].Thus the cells transformed by acting of oncogenes and quiescence of tumor suppressor genes are driven by self-organization, including deterministic chaos and natural selection to form a complex adaptive system,neoplasm [6].

Interaction between cancer cells and niche

There are two main components in cancer field:transformed cells and the niche. Transformed cells express numerous growth factors that recruit and activate stromal cells, tissue-resident stem cell and bone-marrow-derived cells. These cells may contribute to stromatogenesis, angiogenesis, lymphangiogenesis and neurogenesis, result in the formation of cancer field[23-25]. All transformed cells interact with their physical,chemical, and biological environment, including stromal fibroblasts, immune cells, bone-marrow-derived cells,cytokines and extracellular matrix. There are two types of cancer cell-niche interaction: proximate interaction(cell-cell interaction, including interaction between cancer cells and epithelial-mesenchymal interaction,stroma-epithelial interaction and interaction in a paracrine manner) and cell interaction at a distance. The interaction between cells and their environment evoke many kinds of effects, inducing gene expression, proliferation,differentiation, and apoptosis, or they die immediately[26-28]. As the concept of the cancer development, the effects of interaction between cancer cells and niche may be divided into two types: permissive interaction, which provides a permissive soil for tumor cells to survival and proliferation, and instructive interaction, which induces malignant phenotype of tumor cells.

Although the stroma in which carcinomas arise has been previously regarded as a bystander to the clonal expansion and acquisition of malignant characteristics of tumor cells, it is now generally acknowledged that cancer-associated stroma provide a permissive soil for tumor cells. Extracellular matrix plays two-edged roles,inhibitor and promoter, in cancer development.Cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. Permissive interaction between cancer cells and extracellular matrix provides the survival signals, and controls the proliferation,differentiation and metastasis of cancer calls [29]. Bone marrow-derived cells have recently been shown to contribute to stromal formation [30] Bone marrowderived cells home to tumor-specific pre-metastatic sites,providing a permissive niche for incoming tumor cells[31]. On the other hand, cancer cells create a permissive soil by extracellular matrix remodeling [29]. For instance,epithelial cancer cells reprogram normal stroma to a tumorigenic stroma through chemokine growth-regulated oncogene 1 (Gro-1). The expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly,Gro-1 is a potent inducer of senescence in stromal fibroblasts and senescent fibroblasts induced by Gro-1 can promote tumor growth [32]. The input of cancer cells into the normal bone marrow may induce modifications of the local microenvironment, favorable for growth and release of carcinoma cells into the systemic circulation,which correlate with the poor prognosis of patients with bone marrow micrometastases [33]. Thus cancer cell is not adapted environment passively, but creates a permissive soil actively.

Recently Wang et al reported that chronic infection of C57BL/6 mice with H. pylori, induced repopulation of the stomach with bone marrow-derived cells.Subsequently, these cells progressed through metaplasia and dysplasia to intraepithelial cancer [34]. Stromal cell derived factor-1 and stem cell factor-1 (two factors identified in mobilization and migration of marrow progenitor cells) were up-regulated in H. pylori infected mice compared with uninfected age-matched controls.Chronic inflammatory microenvironment plays an instructive role in recruiting, transforming and inducing transdifferentiating of bone marrow cells [34]. Moreover,the interaction between cancer cells and bone mesenchymal stem cells could enhance the aggregative ability of cancer cells [35]. This stroma-induced malignant transformation is associated with additional genetic alterations and changes in gene expression [36].Osteoclasts support the survival and proliferation of myeloma plasma cells in vivo and ex vivo.Osteoclast-induced phenotypic changes associated with dedifferentiation [37]. The precursors of cancer stem cells-namely, precancerous stem cells (pCSCs) - have the potential for both benign and malignant differentiation,depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer,they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice [38]. Thus stroma may play an instructive role in recruiting and transforming progenitor cells, and inducing malignant phenotype of tumor cells.

Interaction between tumor and adjacent tissue

Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells and adjacent "normal" microenvironments [39]. Interactions between potentially neoplastic cells and neighbors act as an important microenvironmental control during cancer development. During the premalignant, intraepithelial stage of squamous cell, such interactions induce a state of intraepithelial dormancy in which cancer progression is suppressed. This dormant state can be overcome by altering tissue dynamics in response to the tumor promoter TPA, UV irradiation, decreasing adhesive interactions between tumor cells and adjacent epithelia or enabling tumor cells to interact with basement membrane proteins [40].

Electrode pH (believed to represent tissue extracellular pH primarily) is substantially and consistently lower in tumor than in adjacent tissues and distal cancerous tissues[41]. Mathematical models of invasive cancer based on tumor-induced acidification of the microenvironment are presented by Gatenby and Gawlinski [42-43], it supports that adjacent tissue is subjected to an extracellular pH that is significantly lower than normal. This leads to degradation of the interstitial matrix, loss of intercellular gap junctions and cell necrosis. Tumor cells have an optimal extracellular pH less than that of normal cells and are thus able to thrive in the acidic microenvironment expanding into the space of the dying normal tissue [44]This observation supports the role of malignant melanoma cells in reprogramming the phenotype of adjacent cells. By transforming the microenvironment,melanoma cells ensure the production of a biological niche where they can prosper. MUC5AC, a human mucin gene, overexpress in metaplasia, dysplasia and “normal”epithelium adjacent to squamous cell lung carcinoma[44].

Although interactions between transformed cells and their normal neighbors may suppress the progress of cancer, adjacent tissues may be remodeled by transformed cells to permit the proliferation and aggregation of cancer cells. Surely the adjacent tissues are not the "normal" tissues.

Field change effects of cancer tissue

The significant intratumor heterogeneity has two distinctly different components, one random and one radial component. The radial component of intratumor heterogeneity raises the field change effects in cancer tissue. Firstly, there are fewer vessels in a more ordered branching pattern inside the tumor than in the tumor periphery [45]. Blood flow is lower in the center of tumors than in the periphery. Because of the non-uniform distribution of tumor vasculature, the majority of hypoxic cells are located in the center of tumors [45]. Hypoxia induce multidrug resistance, radio resistance, apoptosis,necrosis and pH gradient, suppress the proliferation and change the metabolism of cancer cells [46]. Necrotic tumor regions are usually very poorly perfused. Necrosis also tends to develop centrally [47]. Secondly, the distribution and the effects of some drugs are different between the center and periphery of tumor [35, 48-50]. It is primarily because of heterogeneity in the supply of drug through the microvasculature [49]. Thirdly, the field change is associated with additional genetic alterations and changes in gene expression. In a study [22], genes changed their expression levels in the periphery relative to the central region: [15] upregulated and seven downregulated [51]. Ameloblastoma has two relatively distinct patterns, an anti-apoptotic proliferating site in the outer layer, and a pro-apoptotic differentiating site in the inner layer. The expression of Bcl-2 is higher in periphery of ameloblastoma than center of ameloblastoma, while the expression of Bax and Bak is lower in periphery of ameloblastoma than center of ameloblastoma [52].Fourthly, some tumors, such as pancreatic cancer and hepatocellular carcinoma, are frequently associated with intense growth of fibrous tissue at the periphery of tumors.The area of stromal tissue at the periphery of the tumors exceeds that at the center [53]. The fifth intratumor heterogeneity is the field change effects of immune response. Significantly higher number of TIA-1 cytolytic cells outside (periphery of the follicle and interfollicular areas) than within the neoplastic follicle in follicular lymphomas [54]. The sixth intratumor heterogeneity is that cells in the tumor periphery are more easer to invasion and metastasis. Because the adjacent tissue is not the “normal” tissue and intratumor heterogeneity raises the field change effects in cancer tissue, cancer field may be divided into three areas: Ⅰarea -center of tumor, Ⅱarea -periphery of tumor and Ⅲ area -adjacent tissue (Figure 2).

Figure 2 Three areas of cancer field.

Cancer field may be divided into three areas: Ⅰ area-center of tumor, Ⅱ area -periphery of tumor and Ⅲ area-adjacent tissue. Although interactions between transformed cells and their normal neighbors may suppress the progress of cancer, adjacent tissues may be remodeled by transformed cells to permit the proliferation and aggregation of cancer cells. Surely the adjacent tissues are not the “normal” tissues. The radial component of intratumor heterogeneity raises the field change effects,such as microvascular density, hypoxia, necrosis, gene expression, immune response, metastasis, distribution and effects of drugs, in cancer field.

Conclusions and future prospects

To portray the complexities of cancer development, we advocate a new conception, cancer field, to describe the complex adaptive system. Cancer field may be divided into center of tumor, periphery of tumor and adjacent tissue. The balance of inhibitors and inducers, including the interaction among cancer cell, niche and adjacent tissue, governs the switch of cancer development, which mimics embryonic development, a dynamic process of self-organization. The radial component of intratumor heterogeneity raises the field change effects, such as microvascular density, hypoxia, necrosis, gene expression,immune response, metastasis, distribution and effects of drugs, in cancer field. This concept of cancer development biology will help us chart comprehensive maps of cancer. Research strategy may be changed from single cancer cell to cancer field, from malignant transform to cancer development biology. It will drive profound changes in how we study this disease experimentally.