Disease of cellular proliferation characterized by uncontrolled cellular proliferation, local tissue invasion, and disseminated metastasis

Cancer is a disease condition characterized by uncontrolled proliferation of abnormal cells that grow into a tumor distinct from its surrounding tissue. Tumors may be benign, in which they do not escape their local context, or malignant, in which tissue boundaries are disrupted and invaded. Malignant disease is associated with metastatic spread, in which a tumor disseminates to distant tissues, and significant patient mortality.

Cancer is a genetic disease that can begin with a single mutation in a single cell. Due to exposure to environmental stressors, such as fine particle pollution, or endogenous stressors, such as aging-associated chronic inflammation, each cell's genome is exposed to potentially mutagenic events, in which the underlying DNA sequence is subject to change and/or degradation. The majority of these mutations will be a) in an inconsequential site of the genome, b) repaired by endogenous DNA repair effectors, or c) lethal to the cell in which they occur. However, in some events, the mutation may not be repaired, not lethal, and occur in a key gene regulating normal cell proliferation, such as p53 or epidermal growth factor receptor (EGFR). When these conditions are met, cancer may occur.

In normal tissues, cell proliferation is tightly regulated by multiple nested layers of feedback and control that either a) prevent a cell from dividing at the inappropriate time or b) rapidly kill off a cell that is trying to divide at the inappropriate time. These layers of proliferation control include cell-intrinsic genetic, epigenetic, and transcriptional factors as well as cell-extrinsic interactions with other cells, such as surveilling immune cells. In order to become a pathological condition, the initiating cancer cell must successfully evade all layers of control above. In order to be lethal, the cancer must then evade all pharmacological treatment, such as ionizing radiation and cytotoxic chemotherapy, in the clinic.

As an initiating cancer cell grows into a clinically-noticeable tumor, it must successfully surmount challenges to survival from the surrounding stromal tissue, immune surveillance, and loss of nutrient supply via tissue disruption. As it does so, a cancer tends to accumulate additional mutations (fostered by reduced "quality control" for DNA replication in rapidly-dividing cancer cells). The majority of these mutations will confer no additional tumorigenicity to a given cancer and are termed "passenger mutations". A minority of mutations will increase the malignancy of a given cancer and are termed "driver mutations" because they increase the relative fitness of the cancer cells in which they appear. Because cancer growth is constrained by tissue architecture, nutrient supply, and immune surveillance, cancer cells compete with one another for survival and access to the resources needed for proliferation. In this manner, an evolutionary pressure is induced such that cancer cell descendants, or "clones", that carry more driver mutations will out-compete their less-fit brethren and spread faster. Immune activity and clinical treatment introduce further evolutionary pressures on malignant cancers, which in turn drives the emergence of cancer phenotypes that suppress immune activation, favor metastasis, and enable treatment resistance.

As cancer emerges from the unique genetic background of each patient that it afflicts, it is a highly heterogeneous disease. While the cancers of the same tissue may exhibit broadly similar pathological characteristics, such the desmoplastic derangement common to most pancreatic ductal adenocarcinomas, there is significant genetic diversity between patients and even within a given tumor, driven both by the genetic background of the patient and the evolutionary competition for driver mutations mentioned above. It is due to these differences that a "cure for cancer" has been so elusive.

Treatment for cancer has historically relied upon the administration of toxic chemicals or radiation in the hopes that, because cancer cells are dividing more rapidly than non-cancerous cells, these toxic agents will prove more lethal in cancer cells than non-cancerous cells. In many patients and especially for early disease, this treatment is effective even if it causes potent side effects in other rapidly-dividing cell types, such as the immune system, gut epithelium, and hair follicles. However, as noted above, if treatment with toxic agents fails to eliminate all cancer cells, clones bearing driver mutations enabling the cancer cell to ignore the treatment mechanism of action may emerge, leading to treatment resistance which, in turn, drives all cancer mortality.

With the advent of cheap genetic sequencing, the field of oncology has begun shifting towards more-targeted treatment, in which a given patient's disease is molecularly profiled to rationally design a treatment regimen to which it is likely to be most sensitive. This has led to the development of cancer therapies that target specific mutations common in particular types of cancer, such as the ALK inhibitors in non-small cell lung cancer. This approach will continue to yield significant therapeutic benefit for common driver mutations, although there also exists a long tail of uncommon driver mutations that will prove more difficult to address in the clinic. These targeted approaches are still in the early phase in the clinic, but have led to substantial treatment success in previously intractable disease. Over time, continued development of molecularly-targeted therapies will lead to the accrual of a library of precision therapeutics from which oncologists can select individualized treatments that lead to pathological complete remissions in ever-greater numbers of patients.

Separately, the advent of high-resolution immune profiling has led to the discovery that the immune status of a given patient is a key determinant of cancer progression. In patients with highly active immune systems and no chronic inflammatory co-morbidities, an unrestrained immune system can keep an incipient tumor in check for many years or even completely eliminate it before it is noticed in the clinic. When the immune system fails to do so, these patients benefit from the use of targeted immunotherapies to inhibit tumor mechanisms of immune escape. However, the tumor microenvironment (TME) is a highly immunologically active site with multiple layers of interaction and feedback control in a stressed environment that antagonizes immune activation. Sustained TME factors can "reprogram" certain elements of the anti-cancer immune response, such as Th1 T-cells to regulatory T-cells, to become "immunosuppressive", leading to a disabled immune system unable to restrain disease progression. Across multiple types of cancer, the emergence of immunosuppressive signals portends worsened prognosis and increased patient death. To this end, the field of immuno-oncology is now developing myriad targeted therapies that alter the activation status of the immune system with the goal of alleviating immunosuppression and stymying further cancer growth. This, too, will ultimately lead to a broad library of targeted therapies from which immuno-oncologists can rationally design combination immunotherapies to re-activate a given patient's immune system and thus increase their response to treatment.




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May 26, 2020
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