Genentech Oncology
We aim to advance the potential of combined pathway modulation in oncology. Through intensive research in both cancer immunity and tumor targets, we aspire to make fundamental scientific discoveries that will provide a comprehensive, personalized approach in the fight against cancer.
Although cancer is a group of highly complex diseases, cancer cells exhibit a set of distinct attributes across tumor types that enable them to grow and metastasize to distant organs.1
Collectively, these hallmark features provide a broad mechanistic framework within which the multistep transformation of a premalignant cell to its lethal metastatic counterpart is understood.1
Tissue invasion and metastasis are integral components in how tumor cells escape from the primary site and disseminate into distant organs. The process of tissue invasion and metastasis is not well understood, but, in general, it involves changes in the way cells attach to other cells and to the extracellular matrix.2
This process has several steps, including2
Molecular cross-talk between tumor cells and neoplastic stroma suggests that metastases do not arise from a cell-autonomous model but require input from surrounding tissue.2
Molecular cancer research into the complexity of metastatic growth also shows that different malignancies exhibit different characteristics2,3:
Tumor cell migration is promoted in part through a paracrine loop involving CSF-1, EGF, and their corresponding receptors, which are differentially expressed on carcinoma cells and macrophages residing in the tumor microenvironment.4
Normal cells have a finite replicative ability. An intrinsic cellular mechanism allows normal cells to divide a finite number of times and blocks cell division beyond a certain limit.2
Cancer cells overcome this by overexpressing telomerase, an enzyme that maintains telomere length, which protects the ends of chromosomes and allows the cell to continue proliferating. This process is also aided in part by the loss of tumor-suppressor genes, such as TP53.2
In recent years, molecular cancer research has uncovered additional functions of telomerase that are independent of telomere maintenance and may aid in tumor growth2:
A shortening of telomere length activates replicative senescence in normal cells; however, tumor cells overcome the finite replicative ability by overexpressing telomerase, an enzyme that maintains telomere length.2,5
Cell proliferation in normal cells is a tightly controlled process wherein the pro- and antiproliferation signals coordinate their activities at the cell-cycle level. Particularly, the G1 phase of the cell cycle is a vital checkpoint wherein the antigrowth signals exert their influence to block cell proliferation.6
Antigrowth signals in normal cells can block proliferation in multiple ways6,7:
However, most cancer cells circumvent normal growth suppressors in order to continue proliferating.2
The 2 tumor suppressors most commonly dysregulated in cancer cells are retinoblastoma protein (Rb) and tumor protein p53 (TP53). In normal tissue, these proteins are part of a large network that controls the cell cycle.2
Rb and TP53 are 2 common tumor suppressors that are inactivated in tumor cells, leading to uncontrolled growth and proliferation.8
Immune surveillance is an essential cellular process that proactively prevents tumor formation in the human body. Preclinical studies have suggested that an active immune system continuously recognizes and eliminates the vast majority of cancer cells before they establish themselves and form a tumor mass.2
However, cancer immuno-editing, an emerging hallmark, includes 3 key phases—elimination, equilibrium, and escape.9
Clinical examples also support this finding, demonstrating that colon and ovarian cancer patients with an increased immune response have a better prognosis than do those patients with a reduced immune response.2
Cancer immuno-editing, an emerging hallmark, comprises 3 key phases—elimination, equilibrium, and escape. Cancer cells that successfully navigate these phases acquire the ability to evade immune destruction.9
Multiple alterations in the genomes of cancer cells serve as the foundation for many oncogenic processes. Cancer cells take advantage of increased rates of mutations in order to accumulate several mutations needed to foster tumorigenesis. They do this through2:
Accumulation of these mutations is accelerated by altering DNA-maintenance machinery, or “caretaker” genes. These genes are responsible for2:
By inactivating or suppressing caretaker genes, tumor cells can increase the rate of mutations and, subsequently, tumorigenesis.2
Analyses of cancer cell genomes also reveal function-altering mutations and demonstrate that genomic instability increases during tumor progression.2
Cancer cells take advantage of mutations in DNA repair pathways to promote genomic instability. Depicted above is one such mechanism, resulting from the defective BRCA signaling pathway.12
In tumor cells, the process of angiogenesis, or the formation of new blood vessels, is critical for sustained tumor growth and metastasis. Tumor angiogenesis is a multistep process and involves signaling input from several pro-angiogenic growth factors.13,14 The moment at which a tumor begins to overexpress pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), is generally referred to as the “angiogenic switch.”13:
Unabated angiogenesis enables tumor expansion and local invasion through13
Molecular cancer research also suggests that metastases can ultimately exit through the new tumor vasculature into systemic circulation.13
Two additional components play a role in tumor neovasculature2:
Tumor angiogenesis is a function of multiple signals from a number of cell types residing in the tumor microenvironment.13
Reprogramming energy metabolism has been identified as an emerging hallmark in cancer cells.2
To sustain uncontrolled proliferation, cancer cells make adjustments to their energy production by2:
Although limiting energy production to the glycolysis phase decreases the amount of adenosine triphosphate (ATP) produced, it also allows cancer cells to divert glycolic intermediates to various pathways, including those required to assemble new cells.2
Molecular cancer research also reveals a number of activating mutations in enzymes found in glioblastoma that confer an advantage to altering tumor cell energetics.15
Additionally, reprogramming energy metabolism is widely applied in clinical settings today through the use of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) technology that helps capture an image of tumors with increased glucose uptake.16
Cancer cells convert available glucose to lactate irrespective of the availability of oxygen (the Warburg effect), thereby diverting glucose metabolites to useful anabolic processes that accelerate cell proliferation.17
Normal cells may initiate apoptosis in response to DNA damage, among other cellular stresses. In contrast, cancer cells are generally less sensitive to similar stresses and tend to avoid apoptosis.18
Apoptosis occurs through 2 pathways: the intrinsic, or mitochondrial, pathway that is initiated by intracellular stresses; and the extrinsic, death-receptor pathway that is initiated by engagement of cell-surface receptors with specific ligands.18
The intrinsic pathway may be important in cancer, as many of the cellular stresses encountered by cancer cells are activators of the intrinsic pathway. These include DNA damage and growth factor deprivation, as well as treatment with chemo- and immunotherapeutics. The intrinsic pathway is tightly regulated by a group of related proteins called the BCL-2 family.
Consistent with its role in the regulation of apoptosis, many cancers are able to resist the apoptotic pathway through dysregulation of BCL-2 family members. Cancer cells are thought to achieve this through 2 main mechanisms: a down-regulation of pro-apoptotic proteins, or an increase in BCL-2 expression.19
Still, cancer cells may even avoid apoptosis further upstream by dampening the stress signals that promote the initiation of the BCL-2 pathway, or conversely, decreasing downstream effector molecules. For example, mutated TP53, which normally can couple cellular stress to increased expression of pro-apoptotic proteins, resulting in cells less sensitive to DNA damage20; down-regulation of caspase-3 has been linked to apoptotic resistance in some tumor types.21
Other cell-death or cell-death–like pathways exist, such as autophagy and necrosis, and may be dysregulated as a means of cancer cell survival, although their specific roles are currently not well understood.18
Growth signaling in normal cells is a highly regulated process wherein proliferative signals are activated whenever necessary and deactivated when no longer necessary; this tight regulation ensures cell homeostasis. However, in cancer cells, this regulation is compromised.2
One of the fundamental traits of cancer cells is their ability to proliferate without a controlled signaling input. They achieve this in a number of ways2:
Recent studies also highlight the ability of cancer cells to disrupt negative feedback loops that constitute a safety mechanism to dampen a signaling pathway whenever a mitogenic signal is hyperactivated. One key example of this is the Ras oncoprotein.2
Tumor cells disrupt negative feedback loops in the oncogenic Ras signaling pathway, leading to sustained proliferative signaling in tumor cells.2
The tumor microenvironment is often infiltrated by innate and adaptive immune system cells that enable tumors to mimic inflammatory conditions seen in normal tissues. Current molecular cancer research indicates that this tumor-associated inflammation might aid in tumor growth.2
Emerging research also indicates that tumor-associated inflammation may aid in tumor growth by supplying the tumor microenvironment with2:
Additionally, inflammation is often seen in early stages of neoplastic disease. Early inflammation can release chemicals into the tumor microenvironment and may lead to genetic mutations that enable and accelerate the formation of a tumor.2
Tumor-associated inflammation may promote tumor growth by supplying the microenvironment with growth factors, survival factors, and factors that promote angiogenesis.2
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Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136(5):823-837. PMID: 19269363
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Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274-284. PMID: 19308067
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Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239-252. PMID: 19279573
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Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis. 2010;31:9-18. PMID: 19887512
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Ringshausen I, Peschel C, Decker T. Cell cycle inhibition in malignant lymphoma: disease control by attacking the cellular proliferation machinery. Curr Drug Targets. 2006;7:1349-1359. PMID: 17073597
Caldon CE, Sutherland RL, Musgrove EA. Cell cycle proteins in epithelial cell differentiation: implications for breast cancer. Cell Cycle. 2010;9:1918-1928. PMID: 20473028
Caldon CE, Sutherland RL, Musgrove EA. Cell cycle proteins in epithelial cell differentiation: implications for breast cancer. Cell Cycle. 2010;9:1918-1928. PMID: 20473028
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Sherr CJ. Principles of tumor suppression. Cell. 2004;116:235-246. PMID: 14744434
Teng MW, Swann JB, Koebel CM, Schreiber RD, Smyth MJ. Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol. 2008;84:988-993. PMID: 18515327
Teng MW, Swann JB, Koebel CM, Schreiber RD, Smyth MJ. Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol. 2008;84:988-993. PMID: 18515327
Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene. 2008;27:3889-3900. PMID: 18317452
Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene. 2008;27:3889-3900. PMID: 18317452
Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836-848. PMID: 17063185
Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836-848. PMID: 17063185
Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci. 2001;114(pt 20):3591-3598. PMID: 11707511
Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci. 2001;114(pt 20):3591-3598. PMID: 11707511
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027. PMID: 15585754
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027. PMID: 15585754
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Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410. PMID: 12778130
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Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537-548. PMID: 19270154
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Chen K, Chen X. Positron emission tomography imaging of cancer biology: current status and future prospects. Semin Oncol. 2011;38:70-86. PMID: 21362517
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Marie SK, Shinjo SM. Metabolism and brain cancer. Clinics (Sao Paulo). 2011;66(suppl 1):33-43. PMID: 21779721
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Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4:139-163. PMID: 15725726
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Letai AG. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer. 2008;8:121-132. PMID: 18202696
Hermann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ. 2006;13:1256-1259. PMID: 16710363
Hermann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ. 2006;13:1256-1259. PMID: 16710363
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Devarajan E, Sahin AA, Chen JS, et al. Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene. 2002;21:8843-8851. PMID: 12483536
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