小児がんの概説

The number of survivors of childhood cancer have been increasing owing to the continuous development of pharmaceutical science, medical science and medical treatment especially in leukemia which is the most dominant cancer type in pediatric cancer, which is such as obesity, hair loss, endocrine dysfunction like growth hormone and deafness. According to recent follow-up report through 26.5 years(1), they are biologically 5-16 older than control group. Based on this biological trait, they had high risk of frailty and died earlier than those with normal biological aging. Of course, maintenance of healthy state in long term after acute medical treatment may exert alleviation of several sequelae and biological aging. However, the medical treatment like the chemotherapy and radiotherapy in acute phase may basically determine these negative clinical results. More concretely, the strong cytotoxicity of these conventional therapies damages both many normal cells and cancer cells. If the number of normal cells damaged through the therapy in acute phase decreases, sequelae and accelerated aging could be alleviated, so the target therapy only reaching cancer cells bring out excellent possibility to improve the whole life of survivor of childhood cancer. Given the long term health and well-being of them, there are a lot of room for improvement of the therapy even if survival rate over 5 years is significantly high. Based on this perspective, cell-type specific drug delivery system stands a excellent chance to improve the care and whole life of children with cancer, because this system could protect the normal cell through the therapy including even dynamic immune cells and lymph nodes due to cytotoxicity against only cancer cells and efficiently deteriorating surrounding cancer microenvironment. Additionally, understanding and scrutinizing the specific trait of pediatric cancer compared to adult cancer is needed to predict availability of cell-type specific drug delivery system and pave an excellent way to reach these drug systems to the pediatric patients who craves state-of-the-art drug. Epidemiology of childhood cancer indicates that more than 65% cancer types are leukemia or brain cancer, and they are rare diseases whose rate is about 1 per 10,000. Why is pediatric cancer rare and epidemiological main cancer type different compared to adult cancer? Probably, rationale based on proved academic and clinical results at least is not pervasive even in the medical expert including cancer field. Below explanation includes hypothesis, because the practical reference for this reason does not exist. There may be several important academic fields to unravel what is difference between pediatric cancer and adult cancer. Organogenesis and morphogenesis related to development of a child may be highly related to explain the specific feature of childhood cancer. Additionally, homeostatic mechanism of normal tissue including tissue repair, immune system and endocrine system is important. And solid cancer model is paradoxically crucial to find the overlooked trait of pediatric cancer. From these key fields and epidemiology, multifaceted analysis could be realized. Evolutionally, a human child gains rigid development in whole body including several organ and brain, of course, which means healthy organogenesis and morphogenesis. What is healthy organogenesis and morphogenesis? Proper cell-types included in each organ proliferates, is differentiated from stem-cell and mesenchymal stem cell stimulates cell-based development including making gene expression modify in a tightly coordinated manner and a properly compartmentalized way, which means maintaining proper cellular lineage, spatial distribution and size for healthy organogenesis. On the other hand, what is the clear feature of solid tumor? Solid tumor tends to break coordinated morphogenesis, resulting complex topology and for example, protrusion lesion on the epithelial layer. From these clear facts, one deduction is possible. In development stage of tissue, more tightly morphogenesis is needed compared to stable phase in adult because size needs to be changed, meaning frequency of dynamically spatial change of cells composing tissue may be higher than stable phase. As children congenitally has rigid morphogenesis, they hardly make tumor develop because tumor needs to break healthy morphogenesis. One of the important concepts in morphogenesis is connectivity of cells through adhesion molecules such as tight junction. On the other hand, the cell-type of tissue homeostasis like stress monitoring, wound healing and dominant formation of healthy cells through making apoptosis of dysfunctional cells is an immune cell. Therefore, in the development stage of overt cancer, immune system is activated because redundant system toward healthy system is stimulated. Redundancy means over activation of immune system like exhausted immune system. However, organization of opened lymph nodes where several immune cell-types such as B cell, T cell, macrophage and dendritic cell is concentrated and connected each other delivers favorable clinical result of cancer patients in broad cancer cell-types. This opened tissue is called tertiary lymphoid structure. This could explain and prove that collective stress from the healthy cells including the cell-type composing tissue and immune cells to cancer cells based on cell connection is effective to protect each tissue from carcinogenesis. However, this deduction may have contradiction. In fact, the epidemiological rate of central nerve system tumor in childhood is high at about 20-30% among whole pediatric cancer, and CNS tumor is defined as solid tumor. One deduction breaking this contradiction can be considered. The structure of central nerve system is less continuous than other organs, so normal morphogenesis of central nerve system is highly specific. This discontinuous morphogenesis may tend to be not resistant to have carcinogenesis and develop tumor tissue. In another perspective, general cellular origin of pediatric brain cancer is neuron, neural crest cell, astrocyte and oligodendrocyte. In initial phase which means the step at nucleation of solid tumor before progression to overt brain cancer, mobility is high, resulting that cancer cell easily evades tightly coordinated system like leukemia. Additionally, colon cancer is relatively high at about 5% among the whole case, and this may be due to be exposed to extreme carcinogenic stress of normal cells compared to the other organ. This strong epigenetic stress may be “the second hit factor” to promote carcinogenesis additional to congenital cancer-related gene which may not be able to progress to overt cancer independently under the control system of childhood. Leukemia is epidemiologically the first ranked pediatric cancer, whose rate among the respective whole cancer is significantly higher than adult one. The histological trait of leukemia is that each cancer cell has high independency and less connected each other. This discontinuity may evade the rigid control system of children, which are relatively easy to develop overt leukemia. For example, signal transduction through connective adhesion materials between composed cells like tight junction, efficient endocrine interaction like extracellular vesicles, soluble factor efficiently recruiting immune cells related to healthy homeostasis like cytokine and chemokine may be hard to be presented in leukemia. Above multidisciplinary hypothesis could only explain the part of the trait of pediatric cancer. As clarified in leukemia, cancer related mutation is emerged at earlier stage in cell lineage. This hypothesis is related to progression from progenitor of cancer to “overt” cancer. Widely known hypothesis in pediatric leukemia is “second hit model”. This means that two potential carcinogenic stress or trigger at least be related to progress to overt cancer. If above mentioned hypothesis is partly correct, how could this be applied to medical treatment through cell type specific delivery system for well-being of patient with pediatric cancer. At first, understanding histological feature of each cancer cell or tumor in detail including many kinds of cell adhesion molecule is highly related to accessibility of conjugated drug with specificity to targeted cell-type. For instance, each cell type is highly exposed in circulation system in leukemia, so accessibility of drug is relatively high compared to solid tumor with surrounding barrier structure such as extracellular matrix and blood barrier. Therefore, it is considered that CAR immune therapy belonging to the target therapy tends to be effective and has been early approved in leukemia, but is difficult to be applied to medical treatment against solid tumor. In pediatric cancer, leukemia is dominant, so cell-type specific drug delivery system could significantly improve acute medical treatment against leukemia. For example, conjugated chemical substance with highly cytotoxicity, which is not otherwise applied to the clinical case for the pediatric patients is also lesion site specific, but not systemic, thereby the systemic normal cell is protected from strong cytotoxicity. This improvement contributes to well-being and health of whole like for the person who have experienced childhood cancer. Generally, drug delivery efficiency of central nerve system cancer is significantly lower than the other region cancer due to blood brain barrier. However, the region-specific delivery in brain may be possible. In brain, molecular mechanism of neural connection is highly specific in each region, because random connection is severely problematic during neural development and homeostasis. Therefore, protocadherin has at least 70 subtypes which is mainly distributed in neural system. Other novel region-specific protein may be found in future study. If brain cancer partly shares reginal phenotype of neural cell, brain cancer may have same region-specific protein in brain. Importantly, original cell-type of neuroblastoma, which is one of the cancer type among embryonal tumor(3) and is mainly (epidemiologically high rate) affected with pediatric patients under 5 years, is neural crest cell differentiating neuron or neuron. The cellular origin of pediatric glioma is neuron, astrocyte and oligodendrocyte. Hence, highly reginal specific proteins like protocadherin may be expressed also in neuroblastoma and the part of glioma, which exerts great opportunity for novel regional target therapy in addition to psychiatric disease or the other neuronal diseases where the neuron with dysfunctional endocrine system such as neurotransmitter becomes direct target in a reginal specific manner. Additionally, not only neural cell, but also microglia and astrocyte which are one of cellular origin of brain cancer is regional specific in central nerve system(2,4), so specific target except for protocadherin would be found in broad cell-types of brain in the future study. The specific regional protein could be utilized as novel target for cell-type specific drug delivery system. Additionally, scrutinizing histological trait of CNS cancer in pediatric case may be important due to the relation of accessibility to each cell type and it is related to select target protein. For example, claudin 18.2 is novel and efficient target of gastric cancer especially in Japanese. Cellular polarity is lost in gastric tumor(29), resulting that connective protein of cells which is generally formed in unopened side wall of epithelial cells is exposed to surrounding. One of connective proteins is claudin 18.2. Therefore, although claudin 18.2 is expressed both on cancer cell and normal cell, drug delivery efficiency of claudin 18.2 is significantly different between these cell-types due to difference of accessibility to this protein. This relative difference of drug accessibility could exert specific drug delivery to cancer lesion. This case indicates importance of scrutinizing and understanding histological feature of tumor and how much relative accessibility of surface substance on cancer cell for surrounding substance changes by histological feature could affect feasibility of cell-type-specific drug delivery system to broad clinical case especially in any pediatric cancer. Additionally, there is important factor which may improve the clinical result especially in pediatric brain cancer, which needs to be explained here. The factor relate to life style like exercise and diet affects cell function through broad pathways. Hunger may significantly improve resilience against oxidant and chemical stress in glia cell. Therefore, immune function against brain tumor may be also improved along with this resilience. Importantly, neuroblastoma cannot use ketone as energy source unlike the other cell-types. At hunger, dominant energy source is changed from glucose to ketone, so neuroblastoma may significantly have lack of energy state. If metabolic trait of neuroblastoma that cannot utilize ketone is correct(5), keeping pediatric patients with neuroblastoma hungry is universal supplemental condition when providing medical treatment including cutting-edge therapy such as using cell-type-specific drug delivery system. In addition, the metabolic trait of the other brain cancer-type such as glioma needs to be scrutinized especially for utilization of ketone at hungry state.