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3D Bioprinting for Anticancer Drug Screening
necrosis of endothelial cells and leaky, disorganized 2.1.3. Other cells
vasculature is responsible for tumor cell extravasation Adipocytes secrete a number of chemicals that allow
and metastasis [35,36] .
them to act as paracrine factor in the treatment of
[48]
2.1. Role of cells in the TME breast and ovarian cancer . Increase in the number of
adipocytes that correlates with obesity leads to instability
(1) Stromal cells and hypoxia in the TME, which causes tumor invasion
Endothelial cells provide nutritional support for tumor and metastasis. The release of factors, such as IL-6 and
growth and development as well as immune system extracellular vesicles, by adipose tissue cause cancer
protection. Antiangiogenic treatment targets endothelial progression by enhancing the tumor cell oncogenic
cells, which are one of the primary targets [37,38] . Both phenotype or stimulating the adjacent normal cells to
normal fibroblasts and cancer-associated fibroblasts adopt a pro-cancer phenotype.
(CAFs) are found in the TME. The normal fibroblasts are Pericytes are multipotent perivascular cells that play
able to transform into a CAF-like phase or completely into an important part in the formation of the vasculature.
CAFs under certain mechanisms, including contacting In addition to having a favorable or negative influence
with signals (Notch signaling or Eph-ephrins signalling), on tumor development, pericytes can preserve blood
undergoing DNA damage (chemotherapy or radiotherapy), vascular permeability, prevent tumor cell dissemination,
physiological stress (disrupted metabolism), and and contribute to metastasis and cancer progression by
accepting inflammatory signals (interleukin [IL]-1, IL-6 altering pericyte/endothelial cell interactions [49-52] .
and tumor necrosis factor [TNF]) . The CAFs release 2.2. ECM in TME
[39]
growth factors and chemokines that help malignant cells
develop and survive while also encouraging other cells to The ECM is an important component of the TME and
migrate to the tumor . contains a diversity of proteins, such as collagen,
[40]
MSCs interact with tumor cells through secreting fibronectin, laminin, vitronectin, tenascin, glycoproteins,
growth hormones or cytokines and transferring proteoglycans, and polysaccharides [52,53] . The chemokines
mitochondria. They contribute to vascular network and angiogenic factors connected to the ECM-tumor
extension by differentiating into vascular pericytes and cell interaction can change the tensile and compressive
smooth muscle cells. They play a role in every step of strength of tumor tissue [54-56] . Upregulation of biological
tumor growth, including evading immune surveillance, factors, such as transglutaminase and lysyl oxidase,
promoting tumor angiogenesis, establishing therapeutic and secretion of proteases (matrix metalloproteases and
resistance, invasion and metastasis, and generation of cysteine proteases) within the TME result in remodeling
stem tumor cells [41,42] . of the ECM, inflammation, angiogenesis, and tumor
progression [57,58] . Based on the ECM modification in the
(2) Immune cells TME, therapeutic treatments against cancer are focused
The most prominent immune cells found in the TME on targeting the ECM. However, there are several factors
are macrophages, which can account for up to 50% of that could interfere with therapeutic treatment, such as
the tumor mass in certain situations . There are two the complex nature of ECM proteins and their isoforms,
[37]
subsets of macrophages in general, which are classically barrier caused by ECM proteins hindering drug delivery,
[59]
activated macrophages (M1 macrophages) and and modulation of immune response .
alternatively activated macrophages (M2 macrophages). The TME is a dynamic environment, and its
M1 macrophages encourage the inflammation response composition, morphological, physical, and mechanical
against tumor cells, while M2 macrophages suppress characteristics influence tumor growth, metastasis, and
the immune function and favor the tumor progression. anticancer medication efficacy. As a result, a detailed
Hence, most tumor-associated macrophages residing in understanding of the interactions between cancer cell
the tumor cells are M2 macrophages, which reduce the and ECM may make it easier to create realistic tumor
phagocytizing ability of tumor cells and promote the models for anticancer drug screening and identification
spread of tumor cells to other tissues and organs. of promising therapeutic candidates.
NK cells recognize and kill tumor cells via 3. Models for anticancer drug screening
the activation of cell surface receptors and alert the
immune system in cases of infection or malignancy. This section describes the features and advantages of
This function makes them highly explored for cancer various cell cultures and animal models used for anticancer
immunotherapy [43,44] . Other immune cells such as T-cells drug screening. Figure 1 represents the progression in
and mastocytes interact with malignant cells that have terms of increasing complexity to recapitulate the TME
been altered, thereby promoting oncogenesis [45-47] . from 2D cell cultures to bioprinted tumor constructs .
[19]
48 International Journal of Bioprinting (2022)–Volume 8, Issue 4