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International Journal of Bioprinting Biomimetic biofabrication of tumors volume

1. Introduction key features needed for the engineering of complex cancer
models. A library of biomaterial inks and 3D bioprinting
Cancer is a chronic multi-factorial disease and is still technologies available for the fabrication of cancer models
among the major leading causes of death worldwide [1,2] . is listed. Ultimately, a comprehensive report of the most
Cancer incidence and mortality are rapidly growing. To relevant literature contributions on 3D bioprinting of
date, 1 in 8 men and 1 in 10 women are anticipated to be tissue-specific models is presented in this review, with
[3]
diagnosed with cancer in their lifetime . Despite recent particular emphasis on metastatic 3D model, to offer a
advancements in the development of new therapies and thorough support for the engineering of bioinspired cancer
clinical initiatives, cancer progression can hardly be slowed models.
down, posing a major challenge to the global health care
system. In addition, the majority of anti-cancer drugs that 2. Tumor microenvironment
resulted in tumor regression during pre-clinical testing
were ultimately found to be ineffective in clinical trials. Over the last two decades, cancer research has proved that
tumors cannot be identified merely as a sole agglomerate of
Thus, the standard pre-clinical cancer models have [11] [12]
limited versatility and accuracy, which are inadequate proliferating malignant cells . Hanahan and Weinberg
attempted to rationalize tumor complexities by describing
to recapitulate complex biological diseases, such as eight distinct hallmarks of cancer as specific functional
cancer . Safe and effective pre-clinical cancer models are abilities acquired by cancer cells during the development
[4]
needed not only for drug screening but also as a tool for of tumors. Cancerous cells should be (i) sustaining
a better understanding of cancer growth and metastasis proliferative signaling, (ii) resisting cell death, (iii) evading
mechanism. Conventional cancer models, such as two- growth suppressors, (iv) enabling replicative immortality,
dimensional (2D) cultured cancer cell lines and animal (v) deregulating cellular energetics and metabolism,
models, can poorly recapitulate the patient-specific (vi) initiating angiogenesis, (vii) activating invasion and
cancerous tissue, invalidating drug testing and drastically metastasis, and (viii) avoiding immune destruction [12,13] .
limiting further development.
Thus, cancer cells can be considered the driving force of
The awareness of these limitations has resulted in the tumor growth and progression, when supported by a
recent ongoing efforts toward the development of three- cooperative variety of factors .
[14]
dimensional (3D) tumor models [5,6] . To date, research Cancer agglomerates are prone to expand and attract
is focusing on designing physiologically relevant 3D a heterogeneous population of cells, ultimately recruited
models that are able to closely resemble the in vivo to shape (Figure 1) a tumor microenvironment (TME) .
[15]
tumor microenvironment and heterogeneity. In light The majority of the hallmarks of cancer are fostered and
of these challenges, new bioengineering technologies sustained by the contribution of stromal cells . Indeed,
[16]
have emerged in the last decade (e.g., biofabrication) TME is typically composed of cancer stem cells (CSCs),
and have been used to engineer platforms to mimic both stromal cells (such as mesenchymal and immune cells,
healthy and diseased organs, ultimately overcoming some endothelial cells) [17-20] , extracellular matrix (ECM) , and a
[21]
of the aforementioned limitations [7,8] . Particularly, 3D plethora of cytokines and growth factors [22,23] . Cancer cells
bioprinting technology has come to the fore for functional are able to direct and manipulate the function of cellular
applications in cancer research, offering multiple strategies and non-cellular components through signaling networks,
to precisely dispense cells and biomaterials to fabricate orchestrating events such as immunosuppression (via
geometrically complex bioengineered structures with high mechanisms including recruitment of immune suppressive
reproducibility . Importantly, in vitro 3D models offer a cells at the tumor site, release immunosuppressive factors,
[9]
plethora of advantages and specifically the tailored design and the activation of immune checkpoints [e.g., PD-
of cancer drugs following the physiological response of L1/PD-1, CTLA-4, LAG-3, IDO1]) that can induce the
cancer patients, with wide application in the new field of apoptosis of T lymphocytes [24-26] , fibroblast recruitment
personalized cancer medicine, such as patient-specific and their transformation into cancer-associated fibroblasts
immunotherapy .
[10]
(CAFs) [27,28] , and ECM remodeling [29,30] , contributing
Crucially, this comprehensive review highlights the to therapeutics resistance. Taken together, these events
urgent need for accurate and functionally relevant 3D eventually result in tumor development and progression
tumor models, showcasing the specific use of biofabrication into metastatic tumors. However, recent advances in cancer
approaches to engineer biomimetics platforms. The therapy have made use of tumor-infiltrating lymphocytes,
complexity of the mutual interactions between cancer harnessing these powerful assets to grow them in large
cells and extracellular components within the tumor numbers before administering these to the patient.
microenvironment is particularly discussed, highlighting Drug research progresses have recently targeted tumor-

Volume 9 Issue 6 (2023) 374 https://doi.org/10.36922/ijb.1022