Perspective: Biophysical regulation of cancerous and normal blood cell lineages in hematopoietic malignancies

Abstract

It is increasingly appreciated that physical forces play important roles in cancer biology, in terms of progression, invasiveness, and drug resistance. Clinical progress in treating hematological malignancy and in developing cancer immunotherapy highlights the role of the hematopoietic system as a key model in devising new therapeutic strategies against cancer. Understanding mechanobiology of the hematopoietic system in the context of cancer will thus yield valuable fundamental insights that can information about novel cancer therapeutics. In this perspective, biophysical insights related to blood cancer are defined and detailed. The interactions with immune cells relevant to immunotherapy against cancer are considered and expounded, followed by speculation of potential regulatory roles of mesenchymal stromal cells (MSCs) in this complex network. Finally, a perspective is presented as to how insights from these complex interactions between matrices, blood cancer cells, immune cells, and MSCs can be leveraged to influence and engineer the treatment of blood cancers in the clinic.

FIG. 1.

Understanding biophysical regulation of different cellular components in blood cancers. The role of extracellular matrix mechanics is highlighted. Green arrows highlight the functions that may benefit cancer treatment, while red arrows indicate the functions that may promote cancer. Biophysical cues from the matrix are known to play important roles in maintaining HSC functions and directing MSC differentiation. HSCs contribute the turnover of immune cells, while MSCs are known to modulate immune cells. However, the dense matrix represents a barrier for immune cells to migrate through and interact with cancer cells. Biophysical cues from the matrix are also known to regulate proliferation and chemoresistance of cancer cells. Additionally, blood cancer cells are known to originate from HSCs when they are mutated, while they also become chemoresistant when they interact with MSCs.

FIG. 2.

Hierarchical organization of normal hematopoiesis and leukemic transformation. A conventional model of normal hematopoiesis is shown on the left where different blood lineages are derived from hematopoietic stem cells (HSCs). HSCs give rise to multipotent progenitors (MPPs), which lose self-renewal capability. MPPs differentiate into common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CLPs produce lymphoid cells [T-cells, B-cells, and Natural Killer (NK)-cells]. CMPs further differentiate into megakaryocyte-erythroid progenitors (MEPs) and granulocyte-monocyte progenitors (GMPs). GMPs produce granulocytes (gran.) and monocytes (mono.), while MEPs generate megakaryocytes (MKs) and erythroid progenitors (EryPs). Fragmentation of mature MKs under shear stress makes platelets, while nucleation of EryPs leads to red blood cells (RBCs). Terminally differentiated cells subsequently egress the marrow and are distributed throughout different organs. A recent example is highlighted where a newly discovered subset of HSCs is exclusively differentiated into the MK lineage (HSC-MK). Leukemia stem cells (LSCs) are derived from the oncogenic transformation of HSCs. However, the transformation of progenitors can also turn them into LSCs depending on oncogenic mutations that define leukemia subtypes. An example is shown where BCR-ABL transforms HSCs but not progenitors to generate LSCs in CML.

FIG. 3.

A schematic of the bone marrow microenvironment with key stromal cell components and biomechanical characteristics. Tissue becomes softer and fluids more viscous when moving inward radially from the surface of the periosteum. Periosteal arteries lining the surface of the periosteum impose high flow rates and shear stresses that decrease as blood moves through transition vessels followed by sinusoids and eventually the central sinus, leading to systemic venous circulation. In marrow, the osteoid and vascular niches promote different cellular phenotypes based on their mechanical attributes. Hematopoietic stem cells (HSCs) are primarily located near sinusoidal vasculature. Mesenchymal stromal cells (MSCs) positive for leptin receptor (LepR⁺) are located at sinusoids and promote active self-renewal of active HSCs (aHSCs), while MSCs positive for neuron-glial antigen 2 (Ng2⁺) near arterioles support HSC dormancy (dHSCs). HSCs differentiate into hematopoietic lineages, which eventually exit the marrow through the central sinus. MSCs can differentiate into adipocytes (Adipo), which limit HSC proliferation, and osteoblasts (OB), which help to maintain HSCs. Diseased and/or fibrotic regions of marrow, such as in primary myelofibrosis, show increased bone formation and enhanced deposition of collagen and infiltration of malignant cells (inset).

FIG. 4.

Effects of matrix stiffness on intercellular forces. The cell (green) adhering to the soft matrix may experience low cortical tension and hence interact weakly with the other cell (orange). As the matrix stiffness increases, cortical tension increases, thereby promoting cell-cell interaction. The sensitivity of this process is described by the parameter E_A, the matrix stiffness in which the cell-cell interaction force is half-maximal (a). When matrix stiffness increases beyond the maximal point (E_M), total cortical tension in the cell adhering the matrix may become saturated (b). However, cortical tension may become polarized towards the side where the cell adheres to the matrix. This process can competitively decrease cortical tension on the other side and decrease the cell-cell interaction force to a certain level with the half-maximal stiffness, E_D (c). This leads to a biphasic relationship between cell-cell and cell-matrix interaction forces. This model may be generalizable where E_A, E_M, and E_D depend on interacting cell types and the matrix. This model can potentially serve as a basic unit to quantitatively understand more complex interactions that involve multiple cells and matrix components.

FIG. 5.

Hypothesized therapeutic strategies against blood cancers by leveraging insights into mechanobiology. (a) The binding of LSCs to MSCs leads to chemoresistance. If the interaction force between LSCs and MSCs is strong, this can polarize cortical tension on MSCs, leading to a weaker interaction between MSCs and HSCs, and hence impaired normal hematopoiesis. Normalizing cortical tension by myosin-II inhibitors may help to equalize LSC-MSC and HSC-MSC binding forces, which can potentially render LSCs chemosensitive, while maintaining HSCs. (b) After allogeneic hematopoietic transplantation in patients with primary myelofibrosis, donor MSCs (yellow) can be delivered via intrabone transplantation after encapsulation in Arg-Gly-Asp (RGD)-modified alginate microgels (red, ∼3 μm thickness) using droplet microfluidics. Donor MSCs in microgels can be initially shielded from the pathological host marrow with bone deposition to prevent mechanoactivation, while secreting soluble factors to suppress GvHD. GvT may also be preserved depending on biophysical and biochemical cues from the microgels. Once the host matrix is remodeled by MMPs from donor MSCs, they can be programmed to egress from the microgels and integrate with the host to maintain donor HSCs.