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Table 1 Lysosomes play crucial roles in cancer development and progression

From: The role of lysosomes in cancer development and progression

Lysosome-associated biological processes or molecules Mechanism Effect on cancer
Recycling of exogenous materials provides energy, lipids and amino acids for cancer cells. H-rasG12V can stimulate membrane ruffling and pinocytosis. Macropinocytosis is a feature of RAS-transformed cells and can provide energy or metabolite precursors and scavenge lipids in Kras-driven cancer cells, such as pancreatic cancer and lung adenocarcinoma Dysregulating cellular energetics
(Atg5, Atg7, ULK1, BECN1)
Intracellular materials or entire organelles can be delivered to the lysosome for catabolism to provide energy or metabolite precursors to support a transformed phenotype. Failure to clear damaged mitochondria will impair tumor progression. In Kras-Lkb1 mutant lung tumors, inhibition of lysosomal activity causes mitochondrial defects and cancer cell death. Autophagy genes are important in cancers. The deletion of autophagy gene Atg5 or Atg7 inhibits the development of invasive cancers in a mouse model of pancreatic cancer driven by activation of oncogenic KrasG12D. In renal cell carcinoma and soft tissue sarcoma, MiT/TFEB escape surveillance by mTORC1 and become constitutively localized to the nucleus to drive gene expression programs for lysosome biogenesis and autophagy Dysregulating cellular energetics
mTORC1 The lysosome plays an important role in nutrient sensing. When nutrients are deficient, cancer cells can inhibit the activation of mTORC1 on the lysosomal membrane and enhance autophagy to provide energy for themselves. It has been shown that the GATOR1 complex, a GAP for RagA/B, is deleted in human cancers. Lysosomal signaling can stimulate transcriptional programs that regulate lipid catabolism under starvation conditions Dysregulating cellular energetics
Lysosome biogenesis
Lysosomal peripheral localization
Premalignant cells evade oncogene-induced senescence to replicate indefinitely. Autophagy-dependent lysosomal processes can process senescence-associated chromatin fragments and maintain senescence-mediated tumor suppression. SV40 transformation, MYC expression, and mutant KRAS expression can increase the expression of cathepsins and glycosidases. Inactivation of p53 results in a lack of cathepsin activation. Lysosomal peripheral localization maintains cell membrane integrity and repair during cancer cell division Promoting the immortalization of cancer cells
Cathepsin-activated MMPs
Lysosome-derived exocytosis
Lysosomal membrane proteins (LAMP-1)
V-ATPase protein
Cathepsins (e.g., cathepsins B, S, and E) and cathepsin-activated MMPs can degrade extracellular matrix to promote local invasion. Lysosome-derived exocytosis of heparinase and cathepsins changes cell shape to promote invasion by cancer cells. Loss of cathepsin B in a mouse model of pancreatic cancer may decrease metastasis to the liver. Cathepsin L may also play a role in bone metastasis. LAMP-1 is highly expressed in highly metastatic tumor cells, especially metastatic colon cancer cells, indicating that lysosomal membrane proteins are important in cell adhesion and migration. The V-ATPase protein located in the lysosomal membrane can cause an acidic tumor microenvironment and promote the activity of hydrolases Activating invasion and metastasis
Cathepsin-activated MMPs
VEGFR2 recycling
Cathepsins and MMPs can promote angiogenesis by remodeling the extracellular matrix and basement membrane. The pro-form of cathepsin D stimulates mitogen-activated protein kinase signaling and angiogenic gene expression. It has been shown that cathepsin K has a role in neovascularization under hypoxic conditions by activating NOTCH1 signaling. The lysosome also functions in regulating endosome-to-plasma membrane recycling of VEGFR2 Promoting angiogenesis
Immune checkpoint recycling and degradation
Exocytosis of secretory lysosome
Lysosomes play a crucial role in regulating tumor immunity. The expression, recycling, and degradation of immune checkpoints, such as CTLA-4 and PD-1, are dictated largely by lysosomal regulation. Secretory lysosomes can impact the function of NK cells and CTL by releasing granzymes, perforin, chemoattractants and so on. Lysosomal exocytosis can increase the surface area of the phagocytosing macrophage and promote engulfment of large particles. TRPMLs can impact immune function by regulating lysosomal exocytosis, endocytosis, and phagocytosis Impairing antitumor immune response
Tumor antigen processing and presentation
Lysosomes play an important role in tumor antigen processing and presentation. The deficiency of autophagy causes p62 (an autophagy adaptor) accumulation in HCC, which results in the generation of ROS through the dampening of NF-κB signaling. P62 accumulation, NF-κB signaling inhibition, and ROS generation can promote tumorigenesis by dampening dendritic cell function and impairing the antitumor immune response Impairing antitumor immune response
Lysosomal iron
Lysosomes can stimulate programmed cell death by the activation of autophagy or the lysosomal protease-dependent activation of caspases. The defect of lysosomes in cancer cells causes the inability to clear dead cell debris, which leads to the survival of neighboring cells. There is crosstalk between the autophagy and apoptosis pathways in cancer. The antiapoptotic protein BCL-2 can promote cancer cell survival by limiting autophagy and preventing autosis. The accumulation of iron in lysosomes creates favorable conditions for ROS formation by Fenton reactions to promote tumorigenesis Resisting cell death
Lysosomal enzymes
Glucocorticoid receptor
Autophagy (ATG7, Beclin 1)
Lysosomes play an important role in tumor initiation stimulated by chronic inflammation. Cathepsin B can cleave trypsinogen-1, cause pancreatitis, and increase pancreatic cancer risk. Heparanase activated in the lysosome can degrade heparin sulfate proteoglycans and thereby regulate the activity of cytokines and growth factors such as TGF-β. Defects in autophagy genes ATG7 and Beclin 1 also cause chronic inflammation and promote spontaneous cancer of the lung, liver and lymphocytes Tumor-promoting inflammation
Autophagy (Beclin, Atg5)
Lysosomal integrity
Autophagy and lysosome activity participate in the maintenance of genome stability. Kidney cells isolated from Beclin 1 + / − Atg5 − / − mice show accumulation of p62 (an autophagy adaptor). Serial passage of these cells leads to alteration of cell ploidy and genomic instability. Because of deficient autophagic flux, cells cannot recycle nucleic acids, leading to nucleotide depletion and DNA damage. Cancer cells are usually aneuploid. Untransformed aneuploid cells show decreased autophagy, which correlates with the degree of karyotypic imbalance. A lack of lysosomal integrity causes leakage of DNAses from the lysosome and promotes tumorigenesis Promoting genome instability
RTK recycling and degradation
Lysosome membrane
Lysosomes can regulate proliferative signaling through the endocytosis, degradation and recycling of RTKs. Autophagy pathways can also regulate proliferative signaling through the uptake and degradation of intracellular RTK signaling mediators. The activation of mTORC1 depends on its correct position to the lysosome membrane surface Sustaining proliferative signaling
M6P/IGF2R M6P/IGF2R is responsible for the proper trafficking of lysosomal hydrolase. Lysosomal hydrolase can be delivered to lysosomes, where signaling factors are processed that play a role in tumor suppression. The expression of M6P/IGF2R in hepatocellular carcinoma is decreased. M6P/IGF2R is also mutated in colon, breast, prostate, kidney, and lung cancers. Mutant M6P/IGF2R leads to mislocalization of hydrolase and fails to activate TGF-β, a class of conserved cytokines that suppress cell proliferation Sustaining proliferative signaling