The Effectiveness And Mechanism Of Tonifying Kidney And Spleen Method On Preventing And Treatment Of Myelosuppression Induced By Adjuvant Chemotherapy Of Colorectal Cancer Ⅱ

Literature review

I. Research progress of Chinese and Western medicine on chemotherapy-induced bone marrow suppression

The latest data released by IARC show that the number of new cases and deaths of malignant tumors in the world continues to grow [1.2], while the incidence and mortality of cancer in my country are also increasing year by year [3-6]. The global cancer burden is increasing day by day.

Chemotherapy, as the cornerstone of tumor treatment, began in the 1940s. In the following decades, a large number of chemotherapy drugs have been introduced. Through continuous screening in animal experiments and clinical practice, the current relatively mature chemotherapy drug regimens and doses have gradually been formed and widely used in the treatment of tumors. Chemotherapy helps to improve patients' DFS and/or Os. Even in the era of targeted therapy and immunotherapy, chemotherapy is still the mainstay of tumor treatment.

The mechanism of action of most chemotherapy drugs lies in their direct damage to DNA molecules, or interference with the synthesis of DNA and RNA [7]. Therefore, chemotherapy drugs have non-specific killing effects on various types of rapidly proliferating and dividing cells in the body, such as hematopoietic stem/progenitor cells in the bone marrow. Damage to bone marrow hematopoietic stem cells (HSCs) can lead to clinical manifestations such as leukopenia, thrombocytopenia, and anemia in peripheral blood, which may increase the risk of infection and bleeding in patients. At the same time, severe bone marrow suppression often leads to a reduction in chemotherapy drugs, delayed chemotherapy, or even termination, which ultimately affects the effect of chemotherapy and long-term prognosis [8]. Therefore, chemotherapy-induced bone marrow suppression is an important issue that cannot be ignored in tumor treatment.

NEW HERBS CISTANCHE FOR  TUMOR TREATMENT

1. Bone marrow hematopoiesis and bone marrow suppression

1.1 Hematopoietic stem cells and hematopoietic microenvironment

Although the occurrence of hematopoietic cells involves multiple sites such as the yolk sac, fetal liver, and aorta-gonad-mesonephros during embryonic development, the main hematopoietic organ in adults is the bone marrow [9,10]. The bone marrow is composed of hematopoietic cells and the hematopoietic microenvironment. Among them, hematopoietic cells include HSCs, hematopoietic progenitor cells (HPCs), and precursors of various lineages.

HSCs have the potential for self-renewal and multidirectional differentiation. Under physiological conditions, most HSCs are in a relatively quiescent state and do not enter the cell cycle; a small number of HSCs undergo asymmetric mitosis to produce a hematopoietic stem cell with the same self-renewal potential as themselves, and a differentiated multipotent progenitor (MPPs), which then differentiate into progenitor cells of various lineages. Under pathological conditions, related genes such as Msi2[¹2], Lis1¹3], Satb1[14] and cell polarity regulators such as Ap2a215] can act on HSCs to maintain the homeostasis of the hematopoietic system by regulating the ratio of symmetric division and asymmetric division. The bone marrow hematopoietic microenvironment (HM), also known as the hematopoietic stem cell niche, is a special environment that supports and regulates the self-renewal, proliferation, differentiation and maturation of hematopoietic stem and progenitor cells[16] and is the environment in which hematopoietic cells survive. According to anatomical division, there are two different niches in the bone marrow: the endosteal niche and the perivascular niche. The former mainly contains quiescent HSCs, while the latter mainly contains functional HSCs17]. Histologically, HM can be divided into four regions: the endosteal region, the subperiosteal region, the central region, and the perivascular region[18]. The composition of HM is relatively complex, mainly including mesenchymal stem cells (BMSCs), stromal stem cells, endothelial cells, fibroblasts, adipocytes, osteoblasts, and osteoclasts[19]. Various cytokines and growth factors secreted by hematopoietic stem cells and non-hematopoietic cells jointly participate in the regulation of the hematopoietic microenvironment on the quiescence, differentiation, and proliferation of hematopoietic stem cells[20].

 1.2 Chemotherapy-induced bone marrow suppression

Bone marrow suppression can be divided into two types: acute myelosuppression and long-term myelosuppression. Acute myelosuppression often occurs within a short period of time after chemotherapy. Hematopoietic growth factors (HGFs), such as granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage-colony stimulating factor (GM-CSF), can be used clinically to promote the recovery of bone marrow hematopoietic function[8]. Long-term myelosuppression, also known as latent myelosuppression, can develop from acute myelosuppression or be caused by repeated chemotherapy. It is mainly caused by chemotherapy damaging the self-renewal ability of HSCs, resulting in a decrease in the reserve of HSCs[21,22]. When latent myelosuppression occurs, it is easy to be ignored because the peripheral blood cell count may not decrease, and then develop into a long-term hematopoietic disorder[22]. Unlike acute bone marrow suppression, when long-term bone marrow suppression occurs, the application of HGFs may further damage the self-renewal ability of HSCs [23,24]. The possible mechanisms of chemotherapy-induced decrease in HSC self-renewal and reserve capacity include the following aspects:

① Chemotherapy-induced cell death and apoptosis lead to a decrease in the number of HSCs, ② Chemotherapy-induced HSC aging leads to changes in the replication ability of HSCs, ③ Chemotherapy damages the hematopoietic microenvironment, leading to a decrease in the self-renewal ability of HSCs [22,25,26]

1.2.1 Chemotherapy-induced HSC apoptosis

Chemotherapy drugs induce HSC apoptosis, which is one of the important mechanisms of chemotherapy-induced bone marrow suppression. Xu Zhengyang et al. [27] found that the apoptosis rate of mouse bone marrow cells increased on the 4th day after 5-Fu modeling (when bone marrow suppression was at its lowest point). Zhao Juhua[28] found that the nucleated cell count of bone marrow in mice modeled by radiotherapy and chemotherapy was significantly reduced, the cell proliferation index of bone marrow nucleated cells decreased, and the apoptosis rate was significantly increased; cytosine arabinoside (Ara-C) and cyclophosphamide (CTX) combined chemotherapy led to transient proliferation and apoptosis of hematopoietic stem cells in the bone marrow of leukemia model mice[29]. However, in the experiment of busulfan-induced bone marrow suppression in mice, no increase in the apoptosis rate of mouse bone marrow mononuclear cells was observed[30]. This suggests that chemotherapeutic drugs may affect HSCs through apoptosis-dependent pathways and pathways other than apoptosis. Different chemotherapeutic drugs may damage the hematopoietic function of the bone marrow through different pathways.

1.2.2 Chemotherapy drugs induce HSCs senescence

After culturing mouse bone marrow cells in an environment containing busulfan for 5 weeks, a large number of bone marrow cells still survived, but the surviving cells could not form granulocyte macrophage colony-forming units. At the same time, the expression of aging-related β-galactosidase and p16 on the surface of these cells increased. β-galactosidase and p16 are markers of aging [31], suggesting that the main mechanism of busulfan-induced bone marrow suppression in mice is to induce premature senescence of HSCs [32]. Further studies [33 found that busulfan-induced cell senescence is related to the Erk and p38 signaling pathways. In addition, telomere consumption [34,35], oxidative stress [36,37], DNA damage [38,39], epigenetic regulation [40], etc. caused by chemotherapy drugs can all lead to the senescence of HSCs.

1.2.3 Chemotherapy drugs cause HM damage

The effects of chemotherapy drugs on HM include the effects on non-hematopoietic cell components and the effects on cytokines, chemokines and adhesion molecules.

BMSCs are important components of the hematopoietic microenvironment and can differentiate into pericytes, myofibroblasts, bone marrow stromal cells, osteocytes, osteoblasts, adipocytes and endothelial cells in the bone marrow. Among them, the osteoblast-adipocyte differentiation of bone marrow mesenchymal cells plays an important role in hematopoietic homeostasis [41,42]: Under normal circumstances, osteoblasts are conducive to hematopoiesis, and adipocytes inhibit bone marrow hematopoiesis; when the body ages or receives stimulation such as chemotherapy, the osteoblast-adipocyte differentiation is unbalanced, resulting in the dominance of adipocyte differentiation, which causes the recovery of bone marrow hematopoietic function after chemotherapy [43]. Therefore, it is currently believed that adipocytes are one of the negative regulatory factors of hematopoiesis[44]. However, some studies have found that after radiotherapy or 5-Fu chemotherapy, there are a small number of adipocytes that secrete stem cell factor (SCF) in the bone marrow[45,46]. The number of osteoblasts in the bone marrow of mice receiving CTX chemotherapy was significantly reduced. Administration of parathyroid hormone (PTH) or RANKL (receptor activator of nuclear factor kappa-B ligand) can promote bone marrow hematopoiesis147; and excessive osteoblasts can also inhibit hematopoiesis[48,49]. This suggests that the effects of adipocytes and osteoblasts on hematopoiesis may have a more complex mechanism.

In addition, various cytokines, chemokines, and adhesion molecules secreted by HSCs and BMSCs into the hematopoietic microenvironment also play an important role in hematopoietic regulation. Chemotherapy can affect these factors: 5-Fu chemotherapy leads to a significant decrease in hematopoietic stimulating factors, such as stromal cell-derived factor (SDF), SCF and GM-CSF [50]; in the serum of mice treated with CTX chemotherapy, G-CSF and GM-CSF decreased, while tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-y) increased [511, interleukin-6 (IL-6) increased and interleukin-1β (IL-1β) decreased [52]; platelet-endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial growth factor (VEGF) in the bone marrow microenvironment of mice treated with acetylphenylhydrazine (APH) and CTX combined modeling increased platelet-endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial growth factor (VEGF) in the bone marrow microenvironment. In addition, the levels of cytokines, such as VEGF, in HSCs and BMSCs decreased[53]. This suggests that the various cytokines secreted by HSCs and BMSCs into the hematopoietic microenvironment may be closely related to bone marrow hematopoiesis.